Full text of DOI:10.1016/S0040-4020(01)00553-1

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 6627±6640
Asymmetric synthesis of a-amino acids from
a,b-ꢀZ)-didehydroamino acid derivatives with
1,2,3,6-tetrahydropyrazin-2-one structure
p
Tomas Abellan, Balbino ManchenÄo, Carmen Najera and Jose M. Sansano
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Departamento de Quõmica Organica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 24 January2001; revised 23 February2001; accepted 22 March 2001
AbstractÐChiral )Z)-a,b-didehydroamino acid )DDAA) derivatives 14, 15 and 16 are obtained from a new chiral iminic cyclic glycine
template with 1,2,3,6-tetrahydropyrazin-2-one structure 10 bycondensation with carbonyl compounds, Eschenmoser's salt and Bredereck's
reagent, respectively. The didehydroalanine derivative 15 and the enaminone 16 can give DDAA derivatives 14 using Heck ole®nation and
vinylic nucleophilic substitution. These DDAA derivatives 14 and 15 undergo diastereoselective cyclopropanation, 1,3-dipolar and Diels±
Alder cycloaddition reactions giving, after hydrolysis, the corresponding cyclic and bicyclic a-amino acids. q 2001 Elsevier Science Ltd.
All rights reserved.
1. Introduction
The increasing number of nonproteinogenic amino acids
)Fig. 1) has prompted the development of new method-
ologies and strategies exclusivelyfocussed on their asym-
metric synthesis.1 a,b-Didehydroamino acids )DDAAs) I
are one of these conformationallyconstrained noncoded
amino acids. Theyact as antimicrobial and phtyotoxic
agents )lantibiotics)2 and, once incorporated in the peptidic
sequence, an enhanced resistance to enzymatic and chemi-
cal degradation of the resulting proteins occurs.2,3 On the
analogyof the nature, which biosynthesises DDAAs I by
dehydration of serine and threonine residues, organic syn-
thesis mainlyuses b-elimination reactions for obtaining
DDAAs. In this way, chiral DDAA derivatives with E )14
and 25) and Z )3,6 4,7 58 and 69) con®guration )Fig. 2) have
Figure 1. Nonproteinogenic a-amino acids.
been diastereoselectivelygenerated using a Wittig-tpye
ole®nation and Knoevenagel condensation from their corre-
sponding chiral glycine templates. The Knoevenagel
condensation reaction of chiral oxazinone 7 with aldehydes
using, by®rst time, phase-transfer catalsyis )PTC) con-
ditions at room temperature, represented a relevant achieve-
ment in order to applythis methodologyin a large-scale
process. The high diastereoselectivity, together with the
mild reaction conditions required, are in contrast with the
reported synthesis of other DDAA derivatives 1±5. Usually,
strong bases )KOBut) and verylow temperatures are needed
Keywords: amino acids; pyrazinones; asymmetric synthesis; phase-transfer
catalysis; DDAA derivatives; Knoevenagel condensation; cyclopropana-
tion; Heck reaction; enaminones; Diels±Alder reaction.
p
Corresponding author. Tel.: 134-96-5903728; fax: 134-96-5903549;
e-mail: cnajera@ua.es
Figure 2. Chiral DDAA derivatives.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00553-1

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T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6628
nonproteinogenic a-amino acids. The previouslydemon-
strated higher stabilityof pryazinones
918 and 10,19 as
well as their reactivityversus the parent oxazinones 7 and
8, also justifythe use of the pyrazinone 10 for this purpose.
2. Results and discussion
The starting N-Boc protected pyrazine-2-one 10 was
obtained, in 77% global yield, following the methodology
described previously for the synthesis of pyrazinone 9.18a
Chiral auxiliary a-aminoketone hydrochloride 11,18a,19
obtained from )S)-valine in 70% overall yield, underwent
N-acylation with the N-Boc-glycine pivalic acid mixed
anhydride generating amide 12 in 97% yield. After depro-
tection in acidic media )HCl/AcOEt) and cyclisation using a
saturated aqueous solution of potassium carbonate, pyrazi-
none 13 was obtained in 90% yield. Final N-Boc protection
was accomplished with di-tert-butyl dicarbonate at 08C in
the presence of substoichiometric amounts of 4-)N,N-
dimethylamino)pyridine )DMAP) affording compound
1020 in 89% yield )Scheme 1).
Figure 3. Chiral cyclic iminic templates with oxazinone and pyrazinone
structures.
in the case of the pinanone derivative 58 and diketopipera-
zine 36 obtaining low diastereoselectivities. A Horner±
Wadsworth±Emmons ole®nation of the corresponding
phosphonate derivatives afforded heterocycles 14 and oxazi-
nones 2,5 while diketopiperazines )DKP) 47 were prepared
bychemical transformation of the ) Z)-alkylideneoxazo-
lones. Chiral DDAA derivatives are veryversatile starting
compounds for the enantiomericallypure synthesis of a
wide series of a-aminoacids.1 For example, 1-aminocyclo-
propanecarboxylic acids )ACCs) II can be obtained bydia-
stereoselective cyclopropanation with diazoalkenes5,7,8b,c,10
and phosphonium11 or sulfoxonium ylides.5,8a,9 As electro-
philic ole®ns, DDAA derivatives 1, 2 and 6 underwent
Diels±Alder cycloaddition reactions with dienophile-
s9a,b,12,13 furnishing, after hydrolysis, bicyclic a-amino
acids III. An example of the 1,3-dipolar cycloaddition reac-
tion has been reported in the synthesis of )2)-cucurbitine
)type IV see Fig. 1), a naturallyoccurring heteroccylic
a-amino acid, from DDAA derivative 2.14a Hydrogenation
reactions of derivatives 3,6 58b and 69a,c using heterogeneous
catalysis yield, after hydrolysis, a-amino acids and its
N-methyl derivatives V. Michael addition reactions allow
to obtain V and VI as well. Thus, the addition of L-selec-
tridew onto 58b and lithium or magnesium cuprates to DKP
315 afforded good diastereoselectivities of monoalkylated
heterocycles. Analogously, radical additions to 316 for
obtaining monoalkylated DKP have been described.
The Knoevenagel condensation reaction of 10 with alde-
hydes )2.5±5.0 equiv.) and acetone )2.5 equiv.) was carried
out under a solid±liquid phase transfer catalysis with potas-
sium carbonate )3 equiv.) and tetra-n-butylammonium bro-
mide )TBAB, 0.1 equiv.) in dichloromethane at room
temperature )Scheme 2 and Table 1). All tested aldehydes
reacted with potassium carbonate except benzaldehyde,
where a 1:1 mixture of sodium and potassium carbonate
was required in order to prevent the partial isomerisation
of the double bond to an all endo conjugated pyrazinone9a
)Table 1, entry5, footnote d). DDAAs derivatives 14 were
obtained in more than 98% de and isolated as single )Z)-
diastereomers in good yields after chromatographic puri®-
cation without anysigni®cant decomposition. The oxazi-
none glycine equivalent obtained from hydroxypinanone,
precursor of compounds 5, is the unique example reported
in the literature8c able to be condensed with acetone, in the
presence of KOBut in THF at 2788C, affording a 10% yield
of the corresponding DDAA derivative. However, pyrazi-
none 10 furnished 14h in 51% yield under these PTC reac-
tion conditions. Reactions with other ketones were
attempted )acetophenone, 3-pentanone and cyclopentanone)
but no reaction was observed in anycase. In the conden-
sation reaction of 10 with acetaldehyde using several reac-
tion conditions like stronger bases )n-BuLi, LHMDS, LDA,
According to these antecedents, and considering the similar
chemical behaviour existing between oxazinones 817 and
pyrazinones 9,18 we will surveyin this work the synthetic
applications of the chiral iminic cyclic glycine derivative
with pyrazinone structure 1019 )Fig. 3) for the synthesis of
Scheme 1. Synthesis of chiral cyclic iminic template 10.

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6629
t-BuOLi and t-BuOK) at low temperatures )from 278 to
08C) almost 1:1 mixtures of )Z)- and )E)-diastereomers
14a were always detected.
The didehydroalanine derivative 159a and the enaminone 16
were also prepared bycondensation reaction. Thus, N,N-
dimethylmethyleneammonium iodide )Eschenmoser's
salt)9,19 )2 equiv.) reacted with 10 in dichloromethane for
Scheme 2. Synthesis of DDAA derivatives 14 byKnoevenagel condensa-
tion.
Table 1. Synthesis of chiral )Z)-a,b-didehydroamino acid derivatives 14
EnltcryoCmaprobuonndy
Product
R1
R2
Yield )%)a
Rfb
[a]D
25c
No.
1
2
3
4
5
CH3CHO )5.0)
14a
14b
14c
14d
14e
CH3
H
88
86
83
47
85
0.70
0.83
0.75
0.77
0.67
2101.3
2179.0
2129.3
290.8
CH3CH2CHO )2.5)
)CH3)2CHCHO )2.5)
)CH3)3CCHO )3.0)
PhCHOd )2.5)
CH3CH2
)CH3)2CH
)CH3)3C
Ph
H
H
H
H
2156.8
6
)2.2)
14f
H
58
0.61
234.7
7
8
)2.2)
14g
14h
H
53
51
0.47
0.75
293.4
159.5
)CH3)2CO )2.5)
Me
Me
a
b
c
d
Based on pyrazinone 10 after puri®cation by¯ash chromatography)silica gel).
Hexane/ethyl acetate 3/2.
In dichloromethane.
A 1:1 mixture of Na2CO3 and K2CO3 was employed.
Scheme 3. Synthesis of the didehydroalanine derivative 15 and the enaminone 16.
4h )Scheme 3) giving derivative 15 in 88% yield through
one pot aminomethylation±elimination process. In
addition, tert-butoxy-bis)dimethylamino)methane )Breder-
eck's reagent) or the cheaper N,N-dimethylformamide
dimethylacetal,21 in 1,2-dimethoxyethane )DME), afforded
)Z)-16 in 96 and 95% yield, respectively )Scheme 3).
Scheme 4. Synthesis of DDAA derivatives 14 using Heck reaction.
Table 2. Synthesis of chiral )Z)-a,b-didehydroamino acid derivatives 14 using Heck arylation reaction
EntryAr±I
Reaction time )h)
Product
Yield )%)a
25c
[a]D
No.
Rfb
1
2
3
4
PhI
20
20
10
20
14e
14i
14j
14k
54d
40
70
56
0.67
0.65
0.60
0.80
2156.8
2489.0
2215.0
2128.3
1-Naphthyl±I
4-MeOC6H4I
2-MeC6H4I
a
Based on 2-pyrazinone 15 after chromatography)silica gel).
n-Hexane/ethyl acetate:3/2.
In dichloromethane.
b
c
d
A 11% of the N-deprotected compound 17e was also isolated.

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6630
Scheme 5. Synthesis of DDAA derivatives 14 and 17 byvinylic nucleophilic substitution of 16.
Table 3. Synthesis of chiral )Z)-a,b-didehydroamino acid derivatives 14 from enaminone 16
EntryRMgX
Reaction time )h)
Product
Yielda
25b
[a]D
No.
Rfc
1
2
3
4
5
Me2CHMgCl
Me3CMgBr
PhMgBr
1-NaphthylMgI
CH2vCHMgBr
24
24
19
24
24
14c
14d
14ed
17ie
14lf
50
44
60
54
31
2129.3
290.8
2156.8
2189.0
232.9
0.75
0.77
0.67
0.50
0.70
a
Based on 2-pyrazinone 4 after chromatography)silica gel).
In dichloromethane.
n-Hexane/ethyl acetate:3/2.
2 equiv. of organomagnesium reagent were required.
Under typical Barbier conditions.
Some decomposition took place during puri®cation.
b
c
d
e
f
Con®gurational assignments of DDAA derivatives 14 and
16 were made from H NMR data )300 and 500 MHz)
nucleophilic substitution onto enaminone 16.24 First, pyra-
zinone 15 reacted with aryl iodides under Jeffery's
conditions22,23,25 using Pd)OAc)2 )5 mol%) and PPh3
)10 mol%) as catalyst in the presence of TBAB )10 mol%)
and potassium carbonate )3 equiv.) in re¯uxing acetonitrile.
DDAA derivatives 14 were diastereoselectivelyobtained in
moderate to good yields )Scheme 4 and Table 2). Electron-
de®cient aryl iodides such as p-nitroiodobenzene and aryl
bromides did not react under this reaction conditions,
however, electron-rich aryl iodides react faster than iodo-
benzene affording good yields in spite of the steric
hindrance showed by o-iodotoluene )Table 2, entries 3
and 4). This result is contrarywith the normal tendency
observed in the Heck arylations with electrophilic ole®ns.26
Although the oxidative addition is the determining step in
the catalytic cycle, the coordination step between the very
low LUMO27 of the alkene 15 and the higher HOMO of the
palladium complex is essential in this coupling reaction.
Using iodobenzene as organic electrophile, a little amount
of the N-deprotected compound 17e was also isolated
)Table 2, entry1, footnote d).
1
obtained from the crude reaction product. For series of
compounds 14, the ole®nic protons ranging between 6.74
and 7.00 ppm belong to )Z)-isomers whilst )E)-isomer
protons are shifted up®eld )6.48±6.73 ppm). Moreover,
for compounds 14 and 16, C±H coupling constants between
the ole®nic protons and the carbonylic carbon )close to
5 Hz) in proton coupled 13C NMR are consistent with the
)Z)-con®guration.8b,9a,c
DDAA derivatives 14 can also be prepared from DDAA
derivatives 15 and 16 through two alternative and comple-
mentaryroutes to the Knoevenagel condensation. Both
processes, which control the con®guration of the C±C
double bond, are based on the alkylation of the dehydro-
alanine 15 byHeck arylation reaction 22,23 and on the vinylic
Enaminone 16 underwent vinylic nucleophilic substitution,
acting as a b-acylvinyl cation 18,28 at 08C byorgano-
magnesium compounds )4 equiv.) affording diastereoselec-
tively) Z)-DDAA derivatives 14 in moderate yields )Scheme
5 and Table 3). When phenylmagnesium bromide was
employed, the corresponding )Z)-DDAA 14e was obtained
in good yield )Table 3, entry 3, footnote d), nevertheless
isopropyl and tert-butylmagnesium chlorides )Table 3,
entries 1 and 2) gave lower yields of products 14. This result
could be justi®ed because both reagents acted as hydride
source, which reacted with enaminone 16 furnishing also
the didehydroalanine derivative 15. Conjugated diene 14l
)Table 3, entry5, footnote f), isolated in 31% yield, was a
verysensitive compound, which could not be accessed by
the Knoevenagel condensation of acrolein with the corre-
sponding enolate of pyrazinone 10. The possibilityto run
Scheme 6. Synthesis of pyrazinones 19 byradical Michael-type addition.
Table 4. Synthesis of monoalkylated derivatives 19 byradical Michael
addition
EntryRI
Reaction time )h)
Product
Yielda )%)
19
dr
1
2
3
4
But
23
21
20
20
19a
19b
19c
19d
23
31
32
30
1:1
3:2
1:1
1:1
Bu
Pri
Bui
a
Determined after column chromatography)silica gel).

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T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6631
Scheme 7. Synthesis of ACC )2)-allo-norcoronamic acid 21.
the reaction under Barbier conditions29 at room temperature
was also tested byusing 1-iodonaphthalene )5 equiv.) and
magnesium powder )10 equiv.) affording deprotected
compound 17i in good yield after puri®cation )Table 3,
entry4, footnote e). When the same strategywas applied
to isopropylmagnesium chloride, a very low yield )less than
20%) of the deprotected product 17c and high amounts of
decomposition products were detected. In general, yields
depicted in Table 3 could not be improved neither using
catalytic amounts nor stoichiometric quantities of copper)I)
iodide at 2788C raising the temperature to 08C. More
nucleophilic organomagnesium compounds such as benzyl,
methyl or butylmagnesium bromides caused N-Boc depro-
tection and subsequent decomposition. Again, the )Z)-
con®guration of the new DDAA derivatives was con®rmed
as described before.
tives 14 was also studied.31 The reaction of 14a )RˆMe) and
14b )RˆEt) with the less toxic and safest Corey's dimethyl-
sulfoxonium methylide,32 prepared with NaH in DMSO,
furnished spiro-compounds 20 as 11:1 )RˆMe) and 23:1
)RˆEt) mixtures of diastereoisomers )Scheme 7). These
ratios were determined byGC, HPLC, 1H- and 13C NMR.
When using DMF instead of DMSO as solvent at 2208C
anyimprovement of the diastereoselectivitywas observed.
Pure major stereoisomers 20a )RˆMe) and 20b )RˆEt)
were isolated after ¯ash chromatographyin 70 and 79%
yield, respectively. The supposed stereochemistry of 20a
and 20b was con®rmed bythe optical rotation of the ACC
21a, obtained from 20a after acidic hydrolysis )Scheme 7).
Many efforts to hydrolyse 20a afforded decomposed
products, onlya 24% yield of allo-norcoronamic acid 21a,
in high enantiomericallypure form ) .98% ee), was
obtained after treatment with 3 M hydrochloric acid, at
1008C during four days )Scheme 7). This ACC is a biosyn-
thetic precursor of plants hormones, acts as enzyme
inhibitor and plays an important role in the regulation of
enzymatic processes in plants.33 Similarly, 21a is the stron-
gest known competitive inhibitor of the ethylene-forming
enzyme )EFE) in mung bean hypocotyls.34
Monoalkylated a-amino acids derivatives could not be
generated from the chiral glycine template 10 due to the
easysecond deprotonation after the ®rst alkylation reaction
affording 3,3-dialkylated 1,2,3,6-tetrahydropyrazin-2-ones.
Other useful strategies for obtaining monoalkylated hetero-
cycles such as hydrogenation of the corresponding DDAA
derivatives 14 [Pd/C, PtO2, Pd)OH)2] and ionic Michael-
type addition reactions onto 14 or 15 gave verydisappoint-
ing results due to the labilityof the tert-butoxycarbonyl
protecting group. However, 15 suffered radical Michael
addition reaction of alkyl iodides )6 equiv.) using triethyl-
1,3-Dipolar cycloaddition reactions using 15 as dipolaro-
phile and in situ generated azomethine ylides derived
from N-benzylglycine and formaldehyde, was performed
in re¯uxing toluene for 1d. Cycloadduct 22 )precursor of
natural product )2)-cucurbitine)14 was detected in the reac-
tion mixture but it could not be puri®ed )Scheme 8). Alter-
natively, the direct hydrolysis of this reaction crude was
attempted, followed byDowex 50X-100 chromatography,
but no traces of the heterocyclic a-amino acid could be
obtained. The same behaviour was observed with the
cycloadduct 23, generated from the thermal 1,3-dipolar
cycloaddition reaction between 15 and isopropyl N-benzyl-
idene alaninate35 )Scheme 8).
borane )3 equiv.) in anhydrous dichloromethane from
2788C to room temperature
16,30
)Scheme 6 and Table 4).
Monoalkylated products 19 were obtained in moderate
yields with very low diastereoselectivity, the best result
being the reaction with n-butyl iodide whose diastereomer
ratio was 3:2 )Table 4, entry2). These dr were determined
1
by H NMR experiments of the crude reaction products.
The diastereoselective cyclopropanation of DDAA deriva-
Didehydroalanine derivative 15 was further tested as dieno-
phile in Diels±Alder cycloaddition reactions )Scheme 9).
The reaction with cyclopentadiene took place diastereose-
lectivelyat room temperature, in toluene for 3 h affording,
after chromatographic puri®cation, cycloadduct 24 in 42%
yield. By other side, cyclohexadiene needed longer reaction
time )6 days) for achieving high reaction conversions at
room temperature. Again, onlyone stereoisomer was
detected from the reaction mixture and spiro-compound
25 was ®nally isolated in 95% yield. 1-Methoxybutadiene
reacted with 15 at 508C for 1 dayachieving a 2:1 mixture of
diastereomers trans-26 and cis-26 in 66% isolated yield.
The presumed absolute con®guration of the endo-adduct
24 was con®rmed later bythe optical rotation of the bicyclic
a-amino acid 27,9a which was isolated in 61% yield by
Scheme 8. Pyrazinone 15 acting as 1,3-dipole.

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T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6632
Scheme 9. Synthesis of the bicyclic a-amino acids.
hydrogenation, followed by acidic hydrolysis of the amide
and imino groups at 1508C for 4 days )Scheme 9). Never-
theless, the same information could not be extracted from
the bicyclic a-amino acid 28 because the hydrogenation of
the carbon±carbon double bond removed the structural key
clue. X-Raydiffraction experiments could not be done due
to the oilynature of adduct 25, so we thought that the reduc-
tion of the imino group and subsequent generation of the
corresponding salt with a chiral carboxylic acid would be a
possible solution for elucidating its stereochemistry.
Surprisingly, amide carbonyl group was completely reduced
with an excess of sodium borohydride in EtOH at room
temperature for 1 day)Scheme 10). The structure and the
more stable conformation of the resulting perhydropyrazine
29 was totallyassigned combining 1H NMR experiments
)COSY, HETCOR, HMQC, HMBC, NOESY and
GOESY) together with molecular mechanics calculations
)Scheme 10).36 The stereochemistryof the endo-29 adduct
was supported bythe observed NOE effects of H c with both
Ha and Hb, and Hd with Hb, and theyare not represented in
Scheme 9 for simplicity. According to these data, the result-
ing structure of 25 was the endo-adduct shown in Scheme 9.
due to the geminal methoxygroup, and second, no coupling
with the vicinal ole®nic proton was observed because the
value of its dihedral angle with the double bond was close to
908. The more stable conformation of the two diastereomers
was obtained from molecular mechanics calculations36
being each one in total concordance with NMR data. The
major stereoisomer trans-26 showed a relative trans con®g-
uration as a result of the endo approach. These assumptions
were supported bycomparing the large 3J H±C coupling
constant between Ha and the carbonyl group )dihedral
angle near to 1808) exhibited by trans-26 with the analogous
one of the cis-26 )dihedral angle close to 608). Small NOE
effects between Ha and Hb, and Ha with the aromatic protons
were onlyobserved in the trans isomer trans-26, as it was
expected from their corresponding conformations.
Enantiomericallypure ) .98% ee) bicyclic a-amino acids
)2)-)1R,2R,4S)-2-aminobicyclo[2.2.1]heptane-2-carboxylic
acid 27 and )2)-)1R,2R,4S)-2-aminobicyclo[2.2.2]octane-
2-carboxylic acid 28 were obtained in 61 and 38% overall
yield )based on pyrazinone 15 and avoiding the intermediate
puri®cation). The general features of these amino acids such
as bulkiness and apolarityof the bicyclic moietyconfer a
maximal resistance to metabolic attack. Furthermore, the
conformational rigidityand the presence of a substituent
on the ring is a veryuseful tool in order to clarifythe
conformational role of substituents in bioreceptorial inter-
actions.38 Particularly, 27 inhibits the transport of nonpolar
amino acids across cell membranes, acts as an insulin
releasing factor and inhibits the ¯avoprotein amino acid
A similar studywas done when 1-methoxy-1,3-butadiene
was allowed to react with 15. The structure of the cyclo-
adducts trans-26 and cis-26 )2:1) was assigned byNMR
experiments and theyare in agreement with the predomi-
nant HOMO)diene)-LUMO )15) interaction,27,37 which
could be justi®ed bytwo facts: ®rst, the H protons in
a
both stereoisomers appears as a singlet shifted down®eld
Scheme 10. Synthesis and more stable conformation of 29.

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6633
oxidases, whereas 28 perturb selectivelythe levels of
neutral amino acids in the cerebral cortex.39
on Schleicher and Schuell F1400/LS silica gel plates and the
spots visualised with UV light at 254 nm. Flash chroma-
tographyemployed Merck silica gel 60 )0.040±0.063 mm).
4.1.1. Synthesis of ꢀ2S)-2-tert-butoxycarbonylamino-3-
methyl-1-phenyl-1-butanone hydrochloride 11. The syn-
thesis of hydrochloride 11 was performed as indicated in the
3. Conclusion
We conclude that 1,2,3,6-tetrahydropyrazin-2-one 10 is a
versatile glycine template for preparing diastereoselectively
)Z)-a,b-didehydroamino acid )DDAA) derivatives using, as
occurred in the case of oxazinone 7, the condensation reac-
tion with aldehydes under mild reaction conditions )PTC,
inorganic bases and room temperature). Yields obtained
starting from pyrazinone 10 are higher than the reported
for the analogous oxazinone 7. Also slightlyhigher dia-
stereoselectivities were observed with this new glycine
template. Synthesis of the enaminone 17 in high yields
and its reactivityas a b-acylvinyl cation, the Heck ole®na-
tion using DDAA derivatives 15 as well as the radical
Michael-type addition, have not been reported in the case
of the oxazinone 7. The diastereoselectivitywas veryhigh in
these reactions except for the 1,4 radical addition. Cyclo-
propanation reaction of the DDAA derivatives 14 was more
stereoselective and ef®cient than the corresponding reaction
carried out with oxazinone derivatives, unfortunately, the
resulting spiro-compounds proved to be veryunstable
giving ACCs in poor yields. Finally, cycloaddition reactions
with dehydroalanine derivative 15 demonstrated than spiro-
compounds, obtained through 1,3-dipolar reaction, are also
verysensitive products. However, Diels±Alder reaction
took place smoothlywith veryhigh endo-selectivityafford-
ing, after hydrolysis, bicyclic a-amino acids improving the
results previouslyobtained with the chiral oxazinone
template. The LUMO of the pyrazinone 15 is lower than
the oxazinone 7,27 which allowed run the reactions at lower
temperatures arising higher selectivity. All these results
con®rm once more that pyrazinones are more reactive and
more stable compounds than the oxazinones being a
versatile precursor for obtaining a wide series of non-
proteinogenic a-amino acids.
25
literature18a using )S)-valine. [a]D ˆ161.4 )cˆ0.65, H2O).
4.1.2. Synthesis of N-1-[ꢀ1S)-1-benzoyl-2-methylpropyl]-
a
2-[ꢀtert-butoxycarbonyl)amino]acetamide 12. To
suspension of freshlyprepared N-Boc-glycine-pivalic acid
mixed anhydride40 )10 mmol) containing triethylamine
)4.17 mL, 30 mmol) at 08C was added hydrochloride 11
)2.13 g, 10 mmol) and the reaction stirred at room tempera-
ture for 3 h. Water )40 mL) and ethyl acetate )30 mL) were
added, the organic phase separated, dried )Na2SO4) and
evaporated in vacuo. The residue was washed with hot
n-hexane yielding ketone 12 )3.18 mg, 97%) as viscous
25
colourless oil. [a]D ˆ220,6 )cˆ0.80, CH2Cl2); Rf 0.35
)n-hexane/ethyl acetate: 3/2); nmax )®lm) 3500±3100
and 1715±1650 cm21; dH 0.77, 1.01 )2d, Jˆ6.7 Hz, 6H,
)CH3)2CH), 1.46 )s, 9H, )CH3)3C), 2.22 )m, 1H,
CH)CH3)2), 3.82 )dd, Jˆ9.5, 5.8 Hz, 2H, CH2), 4.97 )d,
Jˆ10.0, 1H, NHBoc), 5.57 )dd, Jˆ8.4, 3.5 Hz, 1H, CHN)
and 7.08±8.00 )m, 6H, ArH and NHCOCH2); dC 16.46,
19.85 ))CH3)2CH), 28.14 ))CH3)3C), 31.59 )CH)CH3)2),
44.25 )CH2), 57.85 )CHN), 81.66 ))CH3)3C), 125.52,
128.51, 133.67, 135.06 )ArC), 155.97, 169.64 )2£NCO)
and 198.84 )ArCO); m/z)ESI) 335 )M111, 34%). HRMS
calcd for C18H26N2O4: 334.1893. Found: 334.1894.
4.1.3. Synthesis of ꢀ6S)-6-isopropyl-5-phenyl-1,2,3,6-
tetrahydro-2-pyrazinone 13. A solution of ketone 12
)3.70 g, 10 mmol) in a 3 M solution of hydrogen chloride
in ethyl acetate )50 mL) was stirred for 1 h. The solvent was
evaporated, dissolved in 0.1 M hydrochloric acid )10 mL)
and washed with ether )10 mL). The organic phase was
discarded and the aqueous phase was treated with a
saturated solution of K2CO3 )50 mL) and extracted with
ethyl acetate )3£15 mL). The organic phase was separated,
dried )Na2SO4) and evaporated affording pure pyrazinone
13. When cyclisation was not complete in this step )1H
NMR monitoring) the pure mixture was dissolved in
dichloromethane )10 mL) and triethylamine )1.5 mL,
10 mmol) and the resulting solution was stirred overnight
at room temperature. Solvents were evaporated and
compound 13 was obtained )1.80 g, 90%) as a pale yellow
4. Experimental
4.1. General
Melting points were determined with a Reichert Thermovar
hot plate apparatus are uncorrected. IR were recorded on a
Nicolet 510 P-FT and onlythe structurallymost important
peaks are listed. NMR spectra were performed bythe NMR
Service of the Universityof Alicante on a Bruker AC-300
and DRX-500 using CDCl3 as solvent and TMS as internal
standard unless otherwise stated. Optical rotations were
measured on a Jasco DIP-1000 polarimeter. HPLC analyses
were performed on a Shimadzu LC-10AD equipped with an
APEX-silica 5 mm and DAICEL OD-H columns, eluting
with mixtures of acetonitrile/water and n-hexane/isopropyl
alcohol, respectively. Low-resolution electron impact )EI)
mass spectra were obtained at 70 eV on a Shimadzu
QP-5000 and low-resolution electrosprayionisation )ESI)
mass spectra were obtained on a Finnigan VG Platform.
HRMS )EI) were recorded on a Finnigan MAT 95S. Micro-
analyses were performed by the Microanalyses Service of
the Universityof Alicante. Analytical TLC was performed
25
oil. [a]D ˆ16.6 )cˆ1.63, CH2Cl2); Rf 0.35 )ethyl acetate);
n
max )®lm) 3500±3200 and 1740±1680 cm21; dH 0.78, 0.92
)2d, Jˆ7.0 Hz, 6H, )CH3)2CH)), 2.16 )m, 1H, CHCH3), 4.30
)dd, Jˆ22.0, 3.1 Hz, 1H, CH2), 4.58 )dd, Jˆ22.0, 2.4 Hz,
1H, CH2), 4.70 )m, 1H, CHN), 7.20±7.71 )m, 5H, ArH) and
7.81 )br. s, 1H, NH); dC 14.09, 19.13 ))CH3)2CH)), 32.70
)CHCH3), 52.93 )CHN), 60.11 )CH2), 126.68, 128.63,
130.43, 136.49 )ArC), 164.98 )CvN) and 169.54 )CO);
m/z)ESI) 217 )M111, 93%). HRMS calcd for C13H16N2O:
216.1263. Found: 216.1262.
4.1.4. Synthesis of ꢀ6S)-N-1-ꢀtert-butoxycarbonyl)-5-
phenyl-6-isopropyl-1,2,3,6-tetrahydro-2-pyrazinone 10.
Di-tert-butyl-dicarbonate )2.64 g, 11 mmol) dissolved in
THF )6 mL) was added to a stirred solution of 13 )2.16 g,

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6634
10 mmol) and 4-dimethylaminopyridine )70 mg, 0.1 mmol)
in THF )30 mL) at 08C and stirring continued for 90 min at
the same temperature. THF was evaporated under vacuo and
the residue chromatographed )SiO2) eluting with n-hexane
)ESI) 357 )M111, 17%). HRMS calcd for C21H28N2O3:
356.2100. Found: 356.2099.
4.2.3. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-3-[ꢀZ)-
2-methylpropylidene]-5-phenyl-1,2,3,6-tetrahydro-2-
25
yielding 10 )2.8 g, 89%) as a red oil. [a]D ˆ23.5 )cˆ1.10,
25
CH2Cl2); Rf 0.43 )n-hexane/ethyl acetate: 3/2); nmax )®lm)
1780±1700 cm21; dH 0.87, 0.92 ))2d, Jˆ6.7 Hz, 6H,
)CH3)2CH)), 1.59 )s, 9H, )CH3)3C), 2.13 )m, 1H, CHCH3),
4.36, 4.76 )2d, Jˆ21.7 Hz, 2H, CH2), 5.60 )d, Jˆ7.3 Hz,
1H, CHN) and 7.26±7.82 )m, 5H, ArH); dC 19.21, 19.99
))CH3)2CH)), 27.96 ))CH3)3C), 33.07 )CHCH3), 56.26
)CH2), 59.88 )CHN), 84.16 ))CH3)3C), 126.87, 128.76,
130.86, 137.17 )ArC), 151.90 )CvN), 167.97 and 171.00
)2£CO); m/z)ESI) 316 )M1, 50%). HRMS calcd for
C18H24N2O3: 316.1787. Found: 316.1785.
pyrazinone 14c. Pale yellow oil )83%). [a]D ˆ2129.3
)cˆ0.90, CH2Cl2); Rf 0.75 )n-hexane/ethyl acetate: 3/2);
nmax )®lm) 3064, 1770±1716, 1623 and 857 cm21; dH
0.82, 0.88 )2d, Jˆ6.7 Hz, 6H, )CH3)2CHCN), 1.07, 1.15
)2d, Jˆ6.7 Hz, 6H, )CH3)2CHCvC), 1.57 )s, 9H,
)CH3)3C), 2.10 )m, 1H, )CH3)2CHCN), 3.48 )m, 1H,
)CH3)2CHCvC), 5.58 )d, Jˆ6.7 Hz, 1H, CHN), 6.65 )d,
Jˆ9.8 Hz, 1H, CHvC) and 7.42±7.98 )m, 5H, ArH); dC
19.11, 19.82 ))CH3)2CHCN), 22.03, 22.36 ))CH3)2-
CHCvC), 27.04 ))CH3)2CHCvC), 28.09 ))CH3)3C),
35.44 ))CH3)2CHCN), 59.68 )CHCH)CH3)2), 83.40
))CH3)3C), 128.13, 129.56, 131.89, 136.65, 137.66, 144.80
)ArC and CvCH), 153.01 )CvN), 161.65 and 163.97
)2£CO); m/z )ESI) 371 )M111, 2%). HRMS calcd for
C22H30N2O3: 370.2256. Found: 370.2257.
4.2. Synthesis of ꢀZ)-a,b-didehydroamino acids 14 by
condensation reaction with aldehydes. General
procedure
To a solution of pyrazinone 10 )316 mg, 1 mmol) in
anhydrous dichloromethane )5 mL) under an argon atmos-
phere, K2CO3 )407 mg, 3 mmol) )using benzaldehyde a 1:1
mixture of K2CO3/Na2CO3 was required, see text and Table
1) and Bu4NBr )46 mg, 0.1 mmol) were added. The
aldehyde or acetone was then added to the resulting sus-
pension )see Table 1) and stirring continued for 20 h
)compound 14d required 48 h for completion at room
temperature). Solvent was evaporated under vacuo and the
4.2.4. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl-6-isopropyl-3-[ꢀZ)-
2,2-dimethylpropylidene)]-5-phenyl-1,2,3,6-tetrahydro-
25
2-pyrazinone 14d. Pale yellow oil )47%). [a]D ˆ290.8
)cˆ1.00, CH2Cl2); Rf 0.77 )n-hexane/ethyl acetate: 3/2);
nmax )®lm) 3062, 1770±1726, 1630 and 815 cm21; dH
0.83, 0.87 )2d, Jˆ6.7 Hz, 6H, )CH3)2CH), 1.35 )s, 9H,
)CH3)3CCvC), 1.57 )s, 9H, )CH3)3CO), 2.11 )m, 1H,
)CH3)2CH), 5.57 )d, Jˆ6.7 Hz, 1H, CHN), 6.80 )s, 1H,
CvCH) and 7.26±7.97 )m, 5H, ArH); dC 18.98, 19.74
))CH3)2CH), 28.03 ))CH3)3CO), 30.27 ))CH3)3CCvC),
33.65 ))CH3)2CH), 58.33 )CHN), 68.50 ))CH3)3CCvC),
83.63 ))CH3)3CO), 127.21, 128.77, 130.85 136.18, 136.74,
146.60 )ArC and CvCH), 152.48 )CvN), 161.99 and
162.45 )2£CO); m/z )ESI) 385 )M111, 5%). HRMS calcd
for C23H32N2O3: 384.2413. Found: 384.2414.
residue puri®ed bycolumn chromatography)SiO , n-hexane/
2
ethyl acetate: 90/10), affording DDAA derivatives 14.
Physical and analytical data follow:
4.2.1. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-3-[ꢀZ)-ethylidene]-
6-isopropyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone
25
14a. Pale yellow oil )88%). [a]D ˆ2101.3 )cˆ1.90,
CH2Cl2); Rf 0.70 )n-hexane/ethyl acetate: 3/2); nmax )®lm)
3061, 1771, 1720, 1629 and 852, cm21; dH 0.85 [)2d,
Jˆ6.7 Hz, 6H, )CH3)2CH)], 1.58 )s, 9H, )CH3)3C), 2.06
)m, 1H, CH)CH3)2), 2.16 )d, Jˆ7.3 Hz, 3H, CH3CHvC),
5.59 )d, Jˆ6.5 Hz, 1H, CHN), 6.93 )c, Jˆ7.3 Hz, 1H,
CH3CHvC) and 7.27±8.00 )m, 5H, ArH); dC 13.32
)CH3CHvC), 18.83, 19.73 ))CH3)2CH)), 28.03 ))CH3)3C),
34.66 )CH)CH3)2), 58.88 )CHN), 83.65 ))CH3)3C), 127.24,
128.72, 131.03, 134.91, 136.82, 137.92 )ArC and CHvC),
152.36, 161.67 and 162.84 )2£CO and CvN); m/z)ESI) 343
)M111, 4%). HRMS calcd for C20H26N2O3: 342.1943.
Found: 342.1942.
4.2.5. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-5-
phenyl-3-[ꢀZ)-1-phenylmethylidene]-1,2,3,6-tetrahydro-
25
2-pyrazinone 14e. Pale yellow oil )85%). [a]D ˆ2156.8
)cˆ1.20, CH2Cl2); Rf 0.67 )n-hexane/ethyl acetate: 3/2);
nmax )®lm) 3081, 1770±1714, 1608 and 817 cm21; dH
0.92 )2d, 6H, )CH3)2CH), 1.60 )s, 9H, )CH3)3C), 2.15 )m,
1H, )CH3)2CH), 5.66 )d, Jˆ7.0 Hz, 1H, CHN), 7.23±8.08
)m, 11H, ArH and CHvC); dC 18.89, 19.86 ))CH3)2CH),
27.95 ))CH3)3C), 34.66 ))CH3)2CH), 58.61 )CHN), 83.76
))CH3)3C), 127.49, 128.38, 128.88, 129.36, 131.27,
132.43, 134.81, 135.48, 128.83, 136.47 )ArC and CvCH),
152.21 )CvN), 162.16 and 164.49 )2£CO); m/z)ESI) 405
)M111, 5%) and m/z )EI) 304 )M12100, 23%). HRMS
calcd for C25H28N2O3: 404.2100. Found: 404.2099.
4.2.2. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-5-
phenyl-3-[ꢀZ)-propylidene]-1,2,3,6-tetrahydro-2-pyrazi-
25
none 14b. Stickypale yellow oil )86%). [ a]D ˆ2179.0
4.2.6. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-3-[ꢀZ)-N-1-ꢀtert-
butoxycarbonyl)-1H-indolylmethylidene]-6-isopropyl-5-
phenyl-1,2,3,6-tetrahydro-2-pyrazinone 14f. Pale yellow
)cˆ0.90, CH2Cl2); Rf 0.83 )n-hexane/ethyl acetate: 3/2);
nmax )®lm) 3061, 1772±1716, 1625 and 823 cm21; dH
0.83, 0.87 )2d, Jˆ7.3 Hz, 6H, )CH3)2CH), 1.11 )t,
Jˆ7.9 Hz, 3H, CH3CH2), 1.54 )s, 9H, )CH3)3C), 2.13 )m,
1H, CHCH3), 2.60, 2.73 )2m, 2H, CH2), 5.61 )d, Jˆ6.1 Hz,
1H, CHN), 6.73 )t, Jˆ7.9 Hz, 1H, CHvC) and 7.51±8.08
)m, 5H, ArH); dC 13.35 )CH3CH2), 19.08, 19.87
))CH3)2CH)), 21.03 )CH2), 27.96 ))CH3)3C), 35.43
)CH)CH3)2), 59.65 )CHN), 83.38 ))CH3)3C), 128.12,
129.53, 131.87, 137.82, 137.84, 140.20 )ArC and CHvC),
153.01 )CvN), 161.55 )CONBoc) and 163.92 )COO); m/z
25
oil )58%). [a]D ˆ234.7 )cˆ0.40, CH2Cl2); Rf 0.61 )n-hex-
ane/ethyl acetate: 3/2); nmax )®lm) 3063, 1741, 1679 and
845 cm21; dH 0.90 )2d, Jˆ7.0 Hz, 6H, )CH3)2CH), 1.60
)s, 9H, NCO2But), 1.70 )s, 9H, CONCO2But), 2.15 )m,
1H, )CH3)2CH)), 5.70 )d, Jˆ6.6 Hz, 1H, CHN) and 7.20±
8.30 )m, 11H, In-H, CvCH and ArH); dC 18.83, 19.73
))CH3)2CH), 28.03 )2£)CH3)3C), 34.70 ))CH3)2CH), 58.90
)CHN), 85.65 )2£)CH3)3C), 114.56, 115.00, 115.54, 119.00,

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6635
120.83, 122.06, 123.76, 125.00, 127.04, 128.40, 130.10,
138.25 )ArC and CHvC), 151.34 )CvN), 163.39
)2£CO2But) and 173.87 )CONCO2But); m/z)EI) 343
)M12200, 1%), 186 )1), 145 )80), 144 )100), 116 )33), 90
)8), 89 )34), 77 )2), 44 )22) and 41 )20). HRMS calcd for
C32H37N3O5: 543.2733. Found: 543.2730.
4.2.10. Synthesis of ꢀ6S)-N-1-ꢀtert-butoxycarbonyl)-6-iso-
propyl-3-[ꢀZ)-1-dimethylaminomethyliden]-5-phenyl-
1,2,3,6-tetrahydro-2-pyrazinone 16. To a stirred solution
of pyrazinone 10 )316 mg, 1 mmol) in 1,2-dimetoxyethane
)4 mL), was added dimethylformamide dimethylacetal
)200 ml, 1.5 mmol) or tert-butoxy-bis)dimethylamino)-
methane )Bredereck0s reagent) )310 ml, 1.5 mmol) and the
mixture was stirred at 758C for 16 h. Solvent was evaporated
obtaining pure compound 16 )353 mg and 358 mg, 95 and
4.2.7. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-5-
phenyl-3-{ꢀZ)-1-[3,4-bisꢀ4-methylphenylsulfonyloxy)-
phenyl]methylidene}-1,2,3,6-tetrahydro-2-pyrazinone
25
96%, respectively). [a]D ˆ2739.6 )cˆ0.65, CH2Cl2); Rf
25
14g. Stickypale yellow oil )53%). [ a]D ˆ293.4 )cˆ1.60,
0.21 )n-hexane/ethyl acetate: 3/2); nmax )®lm) 3064,
1770±1716, 1623 and 857 cm21; dH 0.84, 0.91 ))2d,
Jˆ7.0 Hz, 6H, )CH3)2CH)), 1.52 )s, 9H, )CH3)3C), 2.11
)m, 1H, )CH3)2CH)), 3.14, 3.54 )2s, 6H, )CH3)2N), 5.41
)d, Jˆ7.3 Hz, 1H, CHN), 7.31±7.99 )m, 5H, ArH) and
7.46 )s, 1H, CvCH); dC 18.78, 20.01 ))CH3)2CH), 28.05
))CH3)3C), 32.26 ))CH3)2CH), 39.90, 47.39 ))CH3)2N),
57.23 )CHN), 82.07 ))CH3)3C), 112.45 )CvCH), 125.96,
127.96, 128.39, 137.78 )ArC), 144.38 )CvCH), 150.45,
152.95 and 163.34 )2£CvO and CvN); m/z)EI) 271
)M12100, 11%), 228 )100), 187 )36), 185 )20), 91 )10),
77 )8) and 44)69). HRMS calcd for C21H29N3O3: 371.2209.
Found: 371.2204.
CH2Cl2); Rf 0.47 )n-hexane/ethyl acetate: 3/2); nmax )®lm)
3097, 1700, 1731, 1400 and 863 cm21; dH 0.90 )2d,
Jˆ6.6 Hz, 6H, )CH3)2CH), 1.60 )s, 9H, )CH3)3C), 2.06
)m, 1H, )CH3)2CH)), 2.46 )s, 6H, 2£CH3Ph), 5.68 )d, Jˆ
6.4 Hz, 1H, CHN) and 7.28±8.29 )m, 17H, ArH and
CvCH); dC 18.92, 19.88 ))CH3)2CH), 21.80 )2£CH3Ph),
28.04 ))CH3)3C), 35.14 ))CH3)2CH), 58.96 )CHN), 84.14
))CH3)3C), 124.94, 125.24, 128.52, 128.82, 129.91,
131.86, 131.89, 131.92, 132.31, 134.94, 135.41, 136.14,
136.75, 141.56, 141.96, 145.66, 145.80, 145.86, 146.11,
146.20 )ArC and CvC), 152.07 )CvN), 161.75 )CO2But)
and )CONBoc). m/z)ESI) 746 )M112, 4%). HRMS calcd
for C39H40N2O9S2: 744.2082. Found: 744.2090.
4.3. Synthesis of ꢀZ)-DDAA derivatives 14 by Heck
reaction of 15 with aryl iodides. General procedure
4.2.8. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-3-ꢀmethylethyl-
idene)-6-isopropyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazi-
25
none 14h. Pale yellow oil )51%). [a]D ˆ159.5 )cˆ1.60,
Pd)OAc)2 )11 mg, 0,05 mmol), PPh3 )26 mg, 0.1 mmol),
Bu4NBr )32 mg, 0.1 mmol), K2CO3 )414 mg, 3 mmol),
methylenic derivative 15 )328 mg, 1 mmol) and the corre-
sponding iodoarene )1.2 mmol), were suspended in aceto-
nitrile )5 mL). The resulting mixture was re¯uxed for times
depicted in Table 2. Acetonitrile was evaporated under
vacuo and water was added )10 mL). The aqueous phase
was extracted with ethyl acetate )3£15 mL), and the result-
ing organic layer was dried )Na2SO4) and evaporated under
vacuo. The residue was puri®ed bycolumn chromatography
)SiO2, n-hexane/ethyl acetate), obtaining DDAA derivatives
14. Physical and analytical data follow:
CH2Cl2); Rf 0.77 )n-hexane/ethyl acetate: 3/2); nmax )®lm)
3062, 1803, 1720, 1651 and 847 cm21; dH 0.79, 0.88 )2d,
Jˆ6.7 Hz, 6H, )CH3)2CH)), 1.48 )s, 6H, )CH3)2CvC), 1.54
)s, 9H, )CH3)3C), 1.93 )m, 1H, CH)CH3)2), 5.41 )d, Jˆ
7.3 Hz, 1H, CHN) and 7.26±7.98 )m, 5H, ArH); dC 19.15,
20.44 ))CH3)2CH)), 26.79 ))CH3)2CvC), 28.02 ))CH3)3C),
34.43 )CH)CH3)2), 60.99 )CHN), 83.17 ))CH3)3C), 127.26,
127.41, 128.47, 128.79, 130.47, 137.99 )ArC and
)CH3)2CvC), 152.17, 166.39 and 168.82 )2£CO, CvN);
m/z)ESI) 357 )M111, 5%). HRMS calcd for C21H28N2O3:
356.2100. Found: 356.2102.
4.2.9. Synthesis of ꢀ6S)-N-1-ꢀtert-butoxycarbonyl)-6-iso-
propyl-3-methylidene-5-phenyl-1,2,3,6-tetrahydro-2-
pyrazinone 15. To a stirred solution of dimethylmethyl-
eneammonium iodide )371 mg, 2 mmol) in anhydrous
dichloromethane )3 mL) was added a solution of 10
)316 mg, 1 mmol) in drydichloromethane )2 mL). The
mixture was stirred at room temperature for 20 h and an
aqueous saturated solution of sodium bicarbonate )10 mL)
was added at 08C. The organic phase was washed with water
)2£15 mL) and the organic layer was dried )Na2SO4) and
evaporated under vacuo obtaining 15 )289 mg, 88%) as a
4.3.1. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-3-[ꢀZ)-
1-ꢀ1-naphthyl)methylidene]-5-phenyl-1,2,3,6-tetrahydro-
2-pyrazinone 14i. Pale yellow oil )40%). [a]D ˆ2489.0
25
)cˆ0.70, CH2Cl2); Rf 0.60 )n-hexane/ethyl acetate: 3/2);
nmax )®lm) 3067, 1716, 1604 and 840 cm21; dH 0.96, 0.98
)2d, Jˆ6.9 Hz, 6H, )CH3)2CH), 1.63 )s, 9H, )CH3)3C), 2.21
)m, 1H, )CH3)2CH), 5.71 )d, Jˆ6.9 Hz, 1H, CHN) and
7.26±8.36 )m, 13H, ArH, CHvC); dC 19.04, 19.94
))CH3)2CH), 28.07 ))CH3)3C), 34.81 ))CH3)2CH), 58.75
)CHN), 83.97 ))CH3)3C), 124.08, 125.21, 125.92, 126.68,
127.57, 127.94, 128.85, 129.89, 130.85, 131.24, 131.31,
132.62, 133.52, 136.42, 136.49 )ArC and CvCH), 152.40
)CvN), 162.24 and 164.94 )2£CO); m/z )EI) 355
)M12100, 3%), 183 )100), 105 )40), 91 )13), 77 )28) and
44 )59). HRMS calcd for C29H30N2O3: 454.2256. Found:
434.2249.
25
pale yellow oil. [a]D ˆ2118.9 )cˆ1.00, CH2Cl2); Rf 0.74
)n-hexane/ethyl acetate: 3/2); nmax )®lm) 3061, 1774±1723,
1642 and 882 cm21; dH 0.85, 0.88 )2d, Jˆ6.7 Hz, 6H,
)CH3)2CH), 1.59 )s, 9H, )CH3)3C), 2.11 )m, 1H,
)CH3)2CH), 5.63 )d, Jˆ6.0 Hz, 1H, CHN), 5.81, 6.33 )2s,
2H, CvCH2) and 7.27±7.97 )m, 5H, ArH); dC 18.80, 19.64
))CH3)2CH), 27.97 ))CH3)3C), 35.08 ))CH3)2CH), 59.70
)CHN), 84.02 ))CH3)3C), 121.76 )CvCH2), 127.34,
128.78, 131.40, 136.28, 143.85 )ArC and CvCH2),
152.06 )CvN), 161.17 and 165.58 )2£CO); m/z )ESI) 329
)M111, 10%). HRMS calcd for C19H24N2O3: 328.1787.
Found: 328.1789.
4.3.2. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-3-[ꢀZ)-
1-ꢀ4-methoxyphenyl)methylidene]-5-phenyl-1,2,3,6-
tetrahydro-2-pyrazinone 14j. Pale yellow oil )70%).
25
[a]D ˆ2215.0 )cˆ0.20, CH2Cl2); Rf 0.60 )n-hexane/
ethyl acetate: 3/2); nmax )®lm) 3059, 1766, 1678, 1600 and
808 cm21; dH 0.92 )2d, Jˆ6.7 Hz, 6H, )CH3)2CH)), 1.60 )s,

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6636
9H, )CH3)3C), 2.15 )m, 1H, )CH3)2CH)), 3.90 )s, 3H,
OCH3), 5.66 )d, Jˆ7.0 Hz, 1H, CHN), and 7.00±8.08 )m,
10H, ArH and CvCH); dC 18.98, 19.98 ))CH3)2CH), 28.07
))CH3)3C), 34.57 ))CH3)2CH), 55.37 )OCH3), 58.59 )CHN),
83.68 ))CH3)3C), 114.09, 116.34, 127.47, 128.88, 128.91,
131.11, 131.50, 133.86, 134.41, 136.77 )ArC and CvCH),
152.45 )CvN), 162.46 )CO2But) and 163.46 )CON); m/z
)EI) 334 )M12100, 100%), 320 )15), 291 )13), 183 )18),
143 )14), 121 )39), 115 )17), 91 )16), 77 )27), 65 )10), 44
)16) and 41 )18). HRMS calcd for C26H30N2O4: 434.2206.
Found: 434.2208.
4.4.2. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-5-
phenyl-3-[ꢀZ)-2-propenylidene]-1,2,3,6-tetrahydro-2-
pyrazinone 14l. Pale yellow oil )31%). [a]D ˆ232.9
25
)cˆ0.80, CH2Cl2); Rf 0.70 )n-hexane/ethyl acetate: 3/2);
nmax )®lm) 3057, 1717, 1600 and 800 cm21; dH 0.78, 0.81
))2d, Jˆ6.9 Hz, 6H, )CH3)2CH)), 1.51 )s, 9H, )CH3)3C),
2.05 )m, 1H, )CH3)2CH)), 5.51 )d, Jˆ10.1 Hz, 1H,
CHvCH2), 5.56 )d, Jˆ6.1 Hz, 1H, CHN), 5.65 )d,
Jˆ16.5 Hz, 1H, CHvCH2), 7.10 )d, Jˆ11.6 Hz, 1H,
CvCHCHvCH2) and 7.38±7.94 )m, 6H, ArH and
CvCHCHvCH2); dC 19.50, 20.03 ))CH3)2CH), 28.04
))CH3)3C), 34.99 ))CH3)2CH), 58.14 )CHN), 83.81
))CH3)3C), 125.40 )CvCHCHvCH2), 127.34, 128.76
)CvCHCHvCH2), 131.28, 131.94, 133.75, 135.63,
136.58 )ArC and CvCHCHvCH2), 152.23 )CvN),
161.83 )CO2But) and 163.35 )CON); m/z)EI) 354 )M1,
4%), 105 )14), 77 )8), 65 )2), 44 )100) and 40 )66).
HRMS calcd for C21H26N2O3: 354.1943. Found: 354.1940.
4.3.3. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-3-[ꢀZ)-
1-ꢀ1-methylphenyl)methylidene]-5-phenyl-1,2,3,6-tetra-
hydro-2-pyrazinone 14k. Pale yellow oil )56%).
25
[a]D ˆ2128.3 )cˆ0.20, CH2Cl2); Rf 0.77 )n-hexane/
ethyl acetate: 3/2); nmax )®lm) 3058, 1768, 1718, 1606 and
851 cm21; dH 0.93 )2d, Jˆ6.5 Hz, 6H, )CH3)2CH)), 1.61 )s,
9H, )CH3)3C), 2.17 )m, 1H, )CH3)2CH)), 2.50 )s, 3H,
CH3Ph), 5.67 )d, Jˆ7.0 Hz, 1H, CHN) and 7.27±8.14 )m,
10H, ArH and CvCH); dC 19.05, 19.96 ))CH3)2CH), 20.38
)CH3Ph), 28.10 ))CH3)3C), 34.75 ))CH3)2CH), 58.69
)CHN), 83.94 ))CH3)3C), 125.69, 127.60, 128.88, 128.91,
129.29, 130.30, 131.30, 132.45, 133.42, 135.63, 136.59,
139.19 )ArC and CvCH), 152.48 )CvN), 162.29
)CO2But) and 166.55 )CON); m/z)EI) 318 )M12100,
74%), 303 )100), 144 )14), 143 )20), 115 )28), 91 )14), 77
)18), 65 )7), 43 )14) and 41 )14). HRMS calcd for
C26H30N2O3: 418.2256. Found: 418.2253.
4.5. Radical Michael addition onto 15 using Et3B and
alkyl iodides. General procedure
To a solution of 15 )328 mg, 1 mmol) and the alkyl iodide
)6 mmol) in anhydrous dichloromethane )3 mL) at 2788C,
was added dropwise Et3B )3 equiv., 1 M in THF). The
resulting mixture was stirred for times indicated in Table
4. Solvent was evaporated and the residue was puri®ed by
column chromatography)SiO 2, n-hexane/ethyl acetate),
obtaining compounds 19 as mixture of diastereoisomers.
Physical and analytical data follow:
4.4. Synthesis of ꢀZ)-DDAA derivatives 14 by vinylic
nucleophilic substitution from enaminone 16. General
procedure
4.5.1. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-3-neo-
pentyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone
19a.
25
Colourless oil )23%). [a]D ˆ136.8 )cˆ2.50, CH2Cl2); Rf
0.74 )n-hexane/ethyl acetate: 3/2); nmax )®lm) 3056, 1718,
1397 and 1375 cm21; dH )mixed isomers) 0.60, 0.70 )2d,
Jˆ6.0 Hz, 6H, )CH3)2CH), 1.10, 1.25 )2d, Jˆ7.0 Hz, 6H,
)CH3)2CH), 1.20 )m, 2H, CH2), 1.35 )s, 9H, CH2)CH3)3C),
1.55 )s, 9H, )CH3)3C), 1.90 )m, 1H, )CH3)2CH), 1.95, 2.45
)m, 1H, CHCH2But), 4.70 )d, Jˆ1.2 Hz, 1H, CHN), 5.60 )t,
Jˆ3.0 Hz, 1H, CHN) and 7.20±8.00 )m, 5H, ArH); dC
)mixed isomers) 18.36, 19.79 )CH3)2CH), 18.88, 19.72
))CH3)2CH), 28.05 )CH2)CH3)3C), 28.15 ))CH3)3C), 34.34
))CH3)2CH), 34.71 ))CH3)2CH), 36.11 )CH2), 58.36 and
58.91 )CHCH2), 62.84 and 75.21 )CHN), 82.09 and 83.65
)CH2)CH3)3C and )CH3)3C), 125.98, 127.24, 127.48,
127.93, 128.73, 130.59, 131.04, 137.48 )ArC), 151.87
)CvN), 165.67 )CO2But) and 171.27 )CHCON); m/z)EI)
286 )M12100, 8%), 229 )27), 215 )100), 187 )35), 131
)25), 91 )25), 77 )19), 44 )17) and 41 )36). HRMS calcd
for C23H34N2O3: 386.2570. Found: 386.2574.
To a solution of enaminone 16 )371 mg, 1 mmol) in anhy-
drous THF )3 mL) under an argon atmosphere was added
dropwise, at 08C, the Grignard reagent and the resulting
mixture was stirred for times depicted in Table 3. A satu-
rated aqueous solution of ammonium chloride was added
)10 mL) and washed with ethyl acetate )3£15 mL). The
organic phase was dried )Na2SO4) and evaporated under
vacuo and the residue was puri®ed bycolumn chroma-
tographyobtaining 14 or 17. For reactions run under typical
Barbier conditions magnesium powder )10 equiv.) and the
corresponding aryl iodide )5 equiv.) were introduced
together in the reaction mixture instead of the Grignard
reagent. Physical and analytical data follow:
4.4.1. ꢀ6S)-6-Isopropyl-3-[ꢀZ)-1-ꢀ1-naphthyl)methylidene]-
5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone
17i.
Pale
25
yellow oil )54%). [a]D ˆ2189.0 )cˆ0.30, CH2Cl2); Rf
0.50 )n-hexane/ethyl acetate: 3/2); nmax )®lm) 3067, 1716,
1604 and 840 cm21; dH 0.89, 1.05 ))2d, Jˆ6.9 Hz, 6H,
)CH3)2CH)), 2.19 )m, 1H, )CH3)2CH)), 5.25 )dd, Jˆ9.0,
3.5 Hz, 1H, CHN), 5.45 )br. s, 1H, NH) and 7.26±8.36
)m, 13H, ArH, CvCH); dC 19.04, 19.94 ))CH3)2CH),
34.81 ))CH3)2CH), 58.75 )CHN), 124.08, 125.21, 125.92,
126.68, 127.57, 127.94, 128.85, 129.89, 130.85, 131.24,
131.31, 132.62, 133.52, 136.42, 136.49 )ArC and CvCH),
152.40 )CvN), 162.24 )CvO); m/z)EI) 355 )M111, 3%),
183 )100), 105 )40), 91 )13), 77 )28) and 44)59). HRMS
calcd for C24H22N2O: 354.4580. Found: 354.4576.
4.5.2. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-6-isopropyl-3-pen-
tyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone
19b.
Colourless stickyoil )31%). Rf 0.74 )n-hexane/ethyl acetate:
3/2); nmax )®lm) 1790±1700 cm21; dH )mixed isomers)
0.60, 0.70 ))2d, Jˆ6.7 Hz, 6H, )CH3)2CH)), 1.05, 1.25
))2d, Jˆ6.7 Hz, 6H, )CH3)2CH)), 0.90, 1.19 )2t, Jˆ6.7 Hz,
3H, CH3CH2), 1.50±1.90 )m, 9H, )CH2)4 and )CH3)2CH)),
1.55 )s, 9H, )CH3)3C), 1.95, 2.50 )2m, 1H, CHPn), 4.73 )d,
Jˆ1.2 Hz, 1H, CHN), 5.60 )d, Jˆ3.0 Hz, 1H, CHN) and
7.30±8.00 )m, 5H, ArH); dC )trans isomer) 14.82
)CH3CH2), 18.36, 19.42 ))CH3)2CH), 19.71, 20.75, 34.33

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6637
)CH3)CH2)3), 28.15 ))CH3)3C), 34.10 ))CH3)2CH), 36.11
)CH2CH), 58.91 )CHCH2), 62.84 )CHN), 82.09 ))CH3)3C),
127.92, 128.37, 129.03, 137.46 )ArC), 151.01 )CvN),
165.67 )CO2But) and 171.27 )CHCON); dC )cis isomer)
14.04 )CH3CH2), 18.87, 19.78 ))CH3)2CH), 19.71, 20.75,
34.33 )CH3)CH2)3), 28.15 ))CH3)3C), 34.10 ))CH3)2CH),
36.11 )CH2CH), 60.66 )CHCH2), 75.21 )CHN), 83.68
))CH3)3C), 127.27, 128.33, 130.58, 136.85 )ArC), 151.01
)CvN), 165.67 )CO2But) and 171.27 )CHCON); m/z)EI)
286 )M12100, 2%), 228 )97), 213 )79), 187 )14), 143 )9),
91 )10), 77 )21), 44 )72) and 41 )100). HRMS calcd for
C23H34N2O3: 386.2570. Found: 386.2574.
Physical and analytical data of the major diastereoisomers
follow:
4.6.1. ꢀ1R,3S,6S)-N-ꢀtert-Butoxycarbonyl)-6-isopropyl-1-
methyl-8-oxo-5-phenyl-4,7-diazaspiro[2.5]-4-octene 20a.
25
Pale yellow oil )70%). [a]D ˆ211.5 )cˆ3.50, CH2Cl2); Rf
0.69 and Rf 0.76 )n-hexane/ethyl acetate: 3/2); nmax )®lm)
3090, 1770, 1716 and 1640 cm21; dH 0.87, 0.89 )2d,
Jˆ6.7 Hz, 6H, )CH3)2CH), 1.33 )d, Jˆ6.1 Hz, 3H,
CH3CHCH2), 1.49 )dd, Jˆ9.2, 3.7 Hz, 1H, CH2), 1.57 )s,
9H, )CH3)3C), 2.08 )m, 2H, CHCH2 and )CH3)2CH), 2.30
)dd, Jˆ9.2, 3.7 Hz, 1H, CH2), 5.63 )d, Jˆ6.1 Hz, 1H, CHN)
and 7.27±7.80 )m, 5H, ArH); dC 13.48 )CH3CHCH2), 18.77,
19.39 ))CH3)2CH), 28.04 ))CH3)3C), 30.44 )CH2), 31.32
)CHCH2), 33.71 ))CH3)2CH), 50.22 )CH2CCO), 59.58
)CHN), 83.42 ))CH3)3C), 126.58, 128.65, 130.35, 137.54
)ArC), 151.75, 165.88 and 171.36 )2£CvO and CvN);
m/z )EI) 356 )M1, 7%), 256 )1), 213 )100), 91 )8), 77 )4),
44 )3). HRMS calcd for C21H28N2O3: 356.2100. Found:
356.2101.
4.5.3. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-3-isobutyl-6-iso-
propyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone 19c.
Colourless oil )32%). Rf 0.72 )n-hexane/ethyl acetate:
3/2); nmax )®lm) 1766±1700 cm21; dH )mixed isomers)
0.75, 1.03, 1.24 )3d, Jˆ6.8 Hz, 12H, )CH3)2CH) and
)CH3)2CHCH2), 1.45 )s, 9H, )CH3)3C), 1.50±2.15 )m, 4H,
2£)CH3)2CH and CH2), 3.30 )t, Jˆ6.7 Hz, 1H, CHCH2),
5.22 )dd, Jˆ9.1, 3.6 Hz, 1H, CHN) and 7.31±7.98 )m,
5H, ArH); dC )mixed isomers) 16.43, 20.02, 20.27
))CH3)2CH) and )CH3)2CHCH2), 28.04 )CH2), 28.34
))CH3)3C), 31.62 ))CH3)2CH) and )CH3)2CHCH2), 59.59
)CHCH2,), 79.62 )CHN), 81.43 ))CH3)3C), 128.58, 129.04,
133.57, 135.44 )ArC), 153.10 )CvN), 166.70 )CO2But) and
173.02 )CHCON); m/z)EI) 272 )M12100, 4%), 229 )7),
203 )13), 143 )9), 91 )7), 77 )23), 57 )72), 44 )91) and 41
)100). HRMS calcd for C22H32N2O3: 372.2413. Found:
372.2410.
4.6.2. ꢀ1R,3S,6S)-N-ꢀtert-Butoxycarbonyl)-1-ethyl-6-iso-
propyl-8-oxo-5-phenyl-4,7-diazaspiro[2.5]-4-octene 20b.
25
Pale yellow oil )79%). [a]D ˆ214.5 )cˆ1.25, CH2Cl2);
Rf 0.75 )n-hexane/ethyl acetate: 3/2); nmax )®lm) 1800 and
1710 cm21; dH 0.86, 0.88 )2d, Jˆ7.0 Hz, 6H, )CH3)2CH),
1.06 )t, Jˆ7.3 Hz, 3H, CH3CH2), 1.49 )dd, Jˆ9.5, 3.7 Hz,
1H, CH2CHCH2CH3), 1.56 )s, 9H, )CH3)3C), 1.62±2.16 )m,
4H, CH2CHCH2CH3 and )CH3)2CH), 2.23 )dd, Jˆ9.5,
3.7 Hz, 1H, CH2CHCH2CH3), 5.61 )d, Jˆ6.1 Hz, 1H,
CHN) and 7.26±7.78 )m, 5H, ArH); dC 13.43
)CH3CH2CHCH2), 18.96, 19.67 ))CH3)2CH), 21.89
4.5.4. ꢀ6S)-N-1-ꢀtert-Butoxycarbonyl)-3-isopentyl-6-iso-
propyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone 19d.
Colourless oil )30%). Rf 0.76 )n-hexane/ethyl acetate:3/2);
nmax )®lm) 1766±1650 cm21; dH )mixed isomers) 0.75,
1.03, 1.24 )3d, Jˆ6.8 Hz, 12H, )CH3)2CH) and
)CH3)2CHCH2), 1.45 )s, 9H, )CH3)3C), 1.65±2.20 )m, 6H,
2£)CH3)2CH and )CH3)2CHCH2CH2), 1.95, 2.50 )2m, 1H,
CHCO), 4.81 )d, Jˆ3.5 Hz, 1H, CHN), 5.23 )dd, Jˆ9.1 and
3.6 Hz, 1H, CHN) and 7.31±8.00 )m, 5H, ArH); dC
)mixed isomers)16.43, 20.02, 20.26 ))CH3)2CH) and
)CH3)2CHCH2), 22.33 ))CH3)2CHCH2), 28.34 ))CH3)3C),
31.62 ))CH3)2CH) and )CH3)2CHCH2), 34.33 )CH2CHCO),
59.59 )CHCH2,), 79.63 )CHN), 82.10 ))CH3)3C), 128.57,
129.03, 131.03, 133.57 )ArC), 153.10 )CvN), 165.67
)CO2But) and 171.28 )CHCON); m/z)EI) 386 )M1, 1%),
214 )5), 105 )21), 91 )2), 77 )19), 72 )49), 44 )86) and 41
)100). HRMS calcd for C23H34N2O3: 386.2569. Found:
386.2565.
)CH3CH2CHCH2),
28.07
))CH3)3C),
29.69
)CH3CH2CHCH2), 33.70 ))CH3)2CH), 38.08 )CHCH2),
50.68 )CH2CCO), 59.51 )CHN), 83.42 ))CH3)3C), 126.61,
128.69, 130.34, 137.67 )ArC), 151.73, 165.69 and 171.44
)2£CvO and CvN); m/z )EI) 270 )M12100, 2%), 241 )1),
228 )18), 227 )100), 185 )21), 157 )25), 91 )15), 77 )13), 43
)18), 41 )33). HRMS calcd for C22H30N2O3: 370.2256.
Found: 320.2253.
4.6.3. Synthesis of ꢀ2)-allo-norcoronamic acid ꢀ2)-21.
Hydrolysis of 20a )1 mmol) was performed using 3 M
HCl )3 mL) and 1508C for 4 days. Water was evaporated
under vacuo and excess of propylene oxide )0.7 mL,
10 mmol) and EtOH were added re¯uxing the resulting
solution for 0.5 h. )2)-allo-Norcoronamic acid )2)-21
was obtained as a colourless solid )ee.98%, 28 mg,
24%). [a]D ˆ270,0 )cˆ1, H2O), lit.9a [a]D ˆ269,0
)cˆ1, H2O). dH )D2O)9a 0.68 )t, Jˆ6.7 Hz, 1H, CH2), 0.99
)d, Jˆ6.7 Hz, 3H, CH3), 1.24 )dd, Jˆ9.8, 6.1 Hz, 1H, CH2),
1.45 )m, 1H, CHCH3).
25
20
4.6. Synthesis of cyclopropane derivatives 20. General
procedure
4.6.4. Synthesis of cycloadduct 23. A solution of methyl-
enic derivative 15 )328 mg, 1 mmol) in the presence of iso-
propyl N-benzylidene alaninate )219 mg, 1 mmol) in
toluene )3 mL) was re¯uxed during 1 day. Solvent was
evaporated under vacuo obtaining 23 as pure compound
To a solution of trimethylsulfoxonium iodide )222 mg,
1 mmol) in dryDMSO )0.5 mL) sodium hdyride was
)24 mg, 1 mmol) was carefullyadded stirring the resulting
suspension for 0.5 h. DDAA derivative 14a or 14b )1 mmol)
dissolved in DMSO )0.5 mL) was added at 58C and the
mixture was stirred 0.5 h at room temperature. The product
25
)433 mg, 79%). [a]D ˆ121.3 )cˆ0.60, CH2Cl2); Rf 0.61
)n-hexane/ethyl acetate: 3/2); nmax )®lm) 1731 and
;
was immediatelypuri®ed bycolumn chromatography)SiO
n-hexane/ethyl acetate), affording spiranic 20a or 20b as
,
1100 cm21
dH 0.78, 0.81 )2d, Jˆ7.4 Hz, 6H,
2
)CH3)2CHCH), 1.30 )d, Jˆ4.0 Hz, 6H, CO2CH)CH3)2),
11:1 and 23:1 mixtures of diastereoisomers, respectively.
1.58 )s, 9H, )CH3)3C), 1.64 )s, 3H, CH3), 2.05 )m, 1H,

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6638
)CH3)2CH), 2.60, 2.86 )2d, Jˆ13.2 Hz, 2H, CH2), 4.91 )s,
1H, CHPh), 5.17 )d, Jˆ5.7 Hz, 1H, CHN), 5.20 )m, 1H,
CO2CH)CH3)2) and 7.06±7.67 )m, 11H, ArH and NH); dC
18.81, 19.63 ))CH3)2CHCH), 21.72, 21.73 )CO2CH)CH3)2),
21.78 )CH3), 28.00 ))CH3)3C), 34.68 ))CH3)2CHCH),
51.92 )CH2), 59.51 )CHN), 65.20 )CCONBoc), 68.75
)CO2CH)CH3)2), 75.46 )CHPh), 76.42 )CCO2Pri), 83.30
))CH3)3C), 126.91, 127.60, 127.64, 127.85, 128.37,
129.00, 130.49, 135.68 )ArC), 151.40 )CvN), 162.60
)CO2But), 172.69 )CONBoc) and 176.18 )CO2Pri); m/z)EI)
548 )M111, 7%), 229 )7), 228 )7), 105 )17), 91 )7), 77 )19),
44 )100) and 40 )97). HRMS calcd for C32H41N3O5:
547.3046. Found: 547.3042.
acetate: 3/2); nmax )®lm) 3040, 1717, 1654, 763 cm21; dH
)trans-26) 0.69, 0.81 )2d, Jˆ7.2 Hz, 6H, )CH3)2CH), 1.46
)s, 9H, )CH3)3C), 1.86±1.94 )m, 2H, H7b and H8), 2.01 )dt,
Jˆ13.7, 5.5 Hz, 1H, H7a), 2.20 )m, 1H, H6b), 2.41 )m, 1H,
H6a), 3.24 )s, 3H, CH3O), 3.87 )br. s, 1H, H3), 5.58 )d,
Jˆ4.6 Hz, 1H, H1), 5.70 )m, 1H, H4), 5.87±5.90 )m, 1H,
H5), 7.31 )m, 1H, ArHpara), 7.35 )m, 2H, ArHmeta) and 7.67
)m, 2H, ArHortho); dH )cis-26) 0.77, 0.78 )2d, Jˆ6.7 Hz, 6H,
)CH3)2CH), 1.50 )s, 9H, )CH3)3C), 1.76 )m, 1H, H7a) 1.91
)m, 1H, H8), 2.16 )m, 1H, H6b), 2.35 )m, 1H, H7b), 2.44 )m,
1H, H6a), 3.27 )s, 3H, CH3O), 4.45 )br. s, 1H, H3), 5.51 )d,
Jˆ6.0 Hz, 1H, H1), 5.70 )m, 1H, H4), 5.87±5.91 )m, 1H,
H5), 7.31 )m, 1H, ArHpara), 7.35 )m, 2H, ArHmeta) and 7.67
)m, 2H, ArHortho); dC )trans-26) 18.50, 19.53 )2C9), 23.03
)C6), 28.04 ))CH3)3C), 30.32 )C7), 34.33 )C8), 58.15
)CH3O), 62.07 )C1), 66.32 )C2), 83.00 )C)CH3)3), 124.47
)C4), 127.14 )ArCortho), 128.54 )ArCmeta), 129.46 )C5),
130.27 )ArCpara), 137.94 )ArCipso), 152.04 )OCON),
164.19 )CvN) and 172.26 )CCvO). dC )cis-26) 18.99,
20.22 )2C9), 22.48 )C6), 28.01 ))CH3)3C), 33.00 )C7),
34.86 )C8), 58.07 )CH3O), 60.65 )C1), 66.60 )C2), 83.14
)C)CH3)3), 125.80 )C4), 127.55 )ArCortho), 127.62 )C5),
128.41 )ArCmeta), 130.23 )ArCpara), 138.15 )ArCipso),
151.79 )OCON), 165.50 )CvN) and 175.14 )CCvO); m/z
)EI) 312 )M12100, 0.1%), 231 )18), 119 )16), 105 )15), 77
)19), 57 )100), 51 )10), 42 )25), 41 )50).
4.7. Synthesis of endo-adducts 24, 25 and 26. General
procedure
A solution of didehydroalanine 15 )328 mg, 1 mmol) and
the corresponding diene )10±20 mmol) in toluene )3 mL)
was stirred at the temperatures and during reaction times
described previously)see text, Section 2). The solvent was
evaporated and the resulting residue was chromatographed
)SiO2, n-hexane/ethyl acetate) affording endo-cycloadducts
24, 25 and 26. Physical and analytical data follow:
25
4.7.1. endo-Adduct 24. Colourless oil )42%); [a]D
ˆ
111.0 )cˆ1.90, CH2Cl2); Rf 0.80 )n-hexane/ethyl acetate:
3/2); nmax )®lm) 3031, 1770, 1650, 693 cm21; dH 0.76, 0.85
)2£d, Jˆ6.7 Hz, 6H, )CH3)2CH), 1.58 )s, 9H, )CH3)3C),
1.59±2.74 )m, 9H, 3£CH2, 2£CHCvC, )CH3)2CH), 5.53
)d, Jˆ5.5 Hz, 1H, CHN), 5.97, 6.36 )2£m, 2H, CHvCH)
and 7.37±7.84 )m, 5H, ArH); dC 18.64, 19.88 ))CH3)2CH),
22.89, 43.31 )CH2CH2), 28.02 ))CH3)3C), 30.40 )CHCvC),
34.09 ))CH3)2CH), 41.23 )CHCCO), 61.63 )CHN), 65.85
)CCO), 67.02 )CH2CCO), 82.85 ))CH3)3C), 125.30,
127.03 )CHvCH), 128.51, 130.28, 134.31, 137.56 )ArC),
152.71 )CvN), 162.06 )CO2But) and 175.89 )CCON); m/z
)EI) 308 )M12100, 8%), 228 )55), 213 )65), 91 )14), 77
)42), 40 )100). HRMS calcd for C25H32N2O3: 408.2413.
Found: 408.2415.
4.7.4. Synthesis of perhydropyrazine 29. To a solution of
endo-adduct 25 )408 mg, 1 mmol) in ethanol )15 mL) was
slowlyadded sodium borohydride )114 mg, 3 mmol) and
stirring continued for 2 days. Solvent was evaporated
under vacuo and water )10 mL) was added. Aqueous
phase was extracted with ethyl acetate )2£15 mL) and the
organic layer was dried )Na2SO4) ®ltered and evaporated
under vacuo affording pure endo-adduct 29 )358 mg,
25
4.7.2. endo-Adduct 25. Colourless oil )95%). [a]D
ˆ
178.1 )cˆ1.15, CH2Cl2); Rf 0.80 )n-hexane/ethyl acetate:
3/2); nmax )®lm) 3083, 1750, 1642 and 690 cm21; dH 0.81,
0.83 )2£d, Jˆ7.3 Hz, 6H, )CH3)2CH), 1.54 )s, 9H,
)CH3)3C), 1.81 )dd, Jˆ11.0, 3.4 Hz, 1H, CH2CCO), 1.89
)dd, Jˆ11.0, 2.5 Hz, 1H, CH2CCO), 2.03 )m, 1H,
)CH3)2CH), 2.38±3.25 )m, 4H, CHCH2CH), 5.53 )d,
Jˆ6.1 Hz, 1H, CHN), 6.21 )dd, Jˆ5.5, 3.1 Hz, 1H,
CHvCH), 6,33 )dd, Jˆ5.5, 3.1 Hz, 1H, CHvCH) and
7.78±7.82 )m, 5H, ArH); dC 19.04, 19.93 ))CH3)2CH),
28.05 ))CH3)3C), 34.09 ))CH3)2CH), 43.55 )CH2CHCvC),
45.07, 49.13 )2£CH2), 56.76 )CHCCO), 61.55 )CHN),
71.66 )CCO), 82.98 ))CH3)3C), 127.08, 128.60, 130.34,
134.97, 137.78, 138.27 )ArC and CvC), 152.47 )CvN),
163.37 )CO2But) and 174.61 )CCON); m/z )EI) 294
)M12100, 0.3%), 228 )100), 227 )68), 213 )31), 185 )66),
91 )9), 77 )20), 41 )79). HRMS calcd for C24H30N2O3:
394.2256. Found: 394.2255.
25
87%) as colourless oil. [a]D ˆ227.0 )cˆ1.00, CH2Cl2);
Rf 0.80 )n-hexane/ethyl acetate: 3/2); nmax )®lm) 3300,
3030, 1770, 1640, 700 cm21; dH 0.82, 1.18 )2£d,
Jˆ7.0 Hz, 6H, )CH3)2CH), 1.22 )m, 1H, H5b), 1.49 )s, 9H,
)CH3)3C), 1.50 )m, 1H, H5a)), 1.51 )m, 1H, H7b), 1.70 )m,
1H, H7a), 1.79, 1.84 )2m, 2H, H8a and H8b), 2.10 )m, 1H,
H12), 2.47 )m, 1H, H9), 2.52 )m, 1H, H6), 2.83 )d,
Jˆ11.3 Hz, 1H, H4b), 3.02 )d, Jˆ11.3 Hz, 1H, H4a), 3.54
)m, 1H, H2), 3.84 )m, 1H, NH), 4.05 )d, Jˆ7.2 Hz, 1H,
H1), 6.06, 6.12 )2m, 2H, H10 and H11) and 7.17±7.27 )m,
5H, ArH); dC 18.59, 20.92 ))CH3)2CH), 19.71 )C8), 24.65
)C7), 28.35 ))CH3)3C), 29.68 )C12), 30.32 )C6), 36.21 )C9),
36.43 )C5), 57.25 )C2), 61.81 )C3), 62.13 )C1), 66.31 )C4),
80.11 ))CH3)3C), 125.70, 126.71, 127.51, 142.00 )ArC),
133.39, 133.89 )C10 and C11) and 156.82 )CO2But); m/z
)EI) 397 )M111, 8%), 105 )18), 77 )17), 43 )100) and 40
)90). HRMS calcd for C25H36N2O2: 396.2777. Found:
396.2774.
4.7.3. Adducts trans-26 and cis-26. Pale yellow oil )66%).
Required for C24H32N2O4: C, 69.95; H, 7.75; N, 6.80.
Found: C, 70.4; H,7.85; N, 6.65%. Rf 0.75 )n-hexane/ethyl

Â
T. Abellan et al. / Tetrahedron 57 ,2001) 6627±6640
6639
Â
)e) Cativiela, C.; Dõaz-de Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517±3599. Highlights of the chemistry
of AMAAs: )f) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 225±277. )g) Seebach, D.; Sting, A. R.; Hoffmann, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2708±2748.
)h) North, M. Contemp. Org. Synth. 1996, 323±343.
)i) Duthaler, R. O. Tetrahedron 1994, 50, 1540±1650.
)j) Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30,
238±264. )k) Williams, R. M. Synthesis of Optically Active
Amino Acids, Pergamon: Oxford, 1989.
Â
2. Ferreira, P. M.; Maõa, H. L. S.; Monteiro, L. S. Tetrahedron
Lett. 1998, 39, 9575±9578.
4.8. Synthesis of the bicyclic a-amino acids 27 and 28.
General procedure
Â
Â
3. )a) Alvarez-Ibarra, C.; CsakyÈ, A. G.; Murcia, M. C. J. Org.
Chem. 1998, 63, 8736±8740. )b) Schmidt, U.; Lieberknecht,
A.; Wild, J. Synthesis 1988, 159±172.
Method A. Bicycle 24 )394 mg, 1 mmol) was hydrogenated
as described in method A and the resulting residue was
treated with 6 M HCl )6 mL) at 1508C for 4 days. Water
was evaporated under vacuo and excess of propylene oxide
)0.7 mL, 10 mmol) and EtOH were added re¯uxing the
resulting solution for 0.5 h. The colourless precipitate was
®ltered obtaining )2)-)1R,2R,4S)-2-aminobicyclo[2.2.1]-
heptane-2-carboxylic acid 27 )86 mg, 61%): 27´HCl
4. )a) Zimmermann, J.; Seebach, D. Helv. Chim. Acta 1987, 70,
1104±1114. )b) Schickli, C. P.; Seebach, D. Liebigs Ann.
Chem. 1991, 655±668.
5. )a) Williams, R. M.; Fegrey, G. J. J. Am. Chem. Soc. 1991,
113, 8796±8806. )b) Williams, R. M.; Fegrey, G. J. J. Org.
Chem. 1993, 58, 6933±6935.
6. )a) Oba, M.; Terandri, T.; Owari, Y.; Imai, Y.; Motoyama, I.;
Nishiyama, K. J. Chem. Soc., Perkin Trans. 1 1998, 1275±
1281. )b) Oba, M.; Nakajima, S.; Nishiyama, K. Chem.
Commun. 1996, 1875±1876.
25
[a]D ˆ212.7 )cˆ0.5, H2O), [lit.9a )2S-enantiomer)
25
[a]D ˆ112.4 )cˆ0.5, H2O)].
Method B. A suspension of the bicyclic pyrazinone 25
)408 mg, 1 mmol) and Pd/C 10% )60 mg) in methanol
)6 mL) was stirred under a hydrogen atmosphere )1 atm)
at room temperature for 9 h. The resulting suspension was
®ltered through a Celite path and the solvent evaporated.
The residue was treated with a cation-exchange resin
Dowex 50X-100 )5 mg) and 0.75 M HCl )6 mL, prepared
in deionised water) in acetic acid )1.6 mL) and toluene
)2.4 mL). The resulting mixture was boiled for 24 h and
then cooled at room temperature and transferred to a
column. The resin was washed with water till neutral pH,
ethanol and ®nallywith 10% aqueous ammonia affording a
suspension of the corresponding amino acid. The solid was
®ltered and washed with ethyl acetate and acetone affording
pure amino acid )2)-)1R,2R,4S)-2-aminobicyclo[2.2.2]oc-
Â
7. Alcaraz, C.; Fernandez, M. D.; de Frutos, M. P.; Marco, J. L.;
Â
Bernabe, M.; Foces-Foces, C.; Cano, F. H. Tetrahedron 1994,
50, 12433±12456.
8. )a) Calmes, M.; Daunis, J.; Escale, F. Tetrahedron:
Â
Asymmetry 1996, 7, 395±396. )b) Cativiela, C.; Dõaz-de
Â
Villegas, M. D.; Galvez, J. A. Tetrahedron: Asymmetry
1992, 3, 567±572. )c) Alami, A.; Calmes, M.; Daunis, J.;
Escale, F.; Jacquier, R.; Roumestant, M.-L.; Viallefont, P.
Tetrahedron: Asymmetry 1991, 2, 175±178.
Â
9. )a) Chinchilla, R.; Falvello, L.; Galindo, N.; Najera, C. J. Org.
Chem. 2000, 65, 3034±3041. )b) Chinchilla, R.; Falvello, L.;
Â
Galindo, N.; Najera, C. Tetrahedron: Asymmetry 1999, 10,
Â
821±825. )c) Chinchilla, R.; Falvello, L.; Galindo, N.; Najera,
C. Tetrahedron: Asymmetry 1998, 9, 2223±2227.
 Â
10. )a) Cativiela, C.; Dõaz-de Villegas, M. D.; Jimenez, A. I.
Â
Tetrahedron: Asymmetry 1995, 6, 177±182. )b) Jimenez,
25
tane-2-carboxylic acid 28 )63 mg, 40%), [a]D ˆ261.3
)cˆ1.00, H2O), )lit.9a [a]D ˆ261.4 )cˆ1.00, H2O)).
25
J. M.; Casas, R.; OrtunÄo, R. M. Tetrahedron Lett. 1994, 35,
5945±5948.
  Â
11. Chinchilla, R.; Najera, C.; Garcõa Granda, S.; Menendez
Acknowledgements
Â
Velazquez, A. Tetrahedron Lett. 1993, 34, 5799±5820.
12. )a) Pyne, S. G.; Safaei-G, J. J. Chem. Res. ,Synop.) 1996, 160±
161. )b) Pyne, S. G.; Safaei, G. J. Aust. J. Chem. 1993, 46, 73±
93. )c) Pyne, S. G.; Dikic, B.; Gordon, P. A.; Skelton, B. W.;
White, A. H. J. Chem. Soc., Chem. Commun. 1991, 1505±
1506.
Â
We thank the Direccion General de Investigacion Cientõ®ca
yTe cnica )DGICYT) of the Spanish Ministerio de
Â
Educacion yCultura )MEC) )PB97-0123 and PB95-0792)
and Generalitat Valenciana )GVDOC00-14-02) for ®nancial
Â
Â
Â
support.
13. For nonchiral systems
Â
1
using chiral catalysts see:
)a) Cativiela, C.; Lopez, P.; Mayoral, J. A. Tetrahedron:
Â
Asymmetry 1991, 2, 1295±1304. )b) Cativiela, C.; Lopez, P.;
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Â
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