Chiral (Z)-α,β-didehydroamino acid derivatives from a new chiral glycine equivalent with a 1,2,3,6-tetrahydropyrazin-2-one structure: Applications to the synthesis of 1-aminocyclopropanecarboxylic acids and bicyclic α-amino acids

Article abstract of DOI:10.1016/S0957-4166(00)00023-9

The new chiral glycine equivalent 9, easily obtained from (+)-α-aminoisovalerophenone and glycine, afforded chiral (Z)-α,β-didehydroamino acid (DDAA) derivatives 13 and 14 with a 1,2,3,6-tetrahydropyrazin-2-one structure. Compounds 13 and 14 were synthesised by reaction of 9 with Eschenmoser's salt and by condensation reactions with aldehydes or acetone under PTC conditions, respectively. The diastereoselective cyclopropanation of 14, followed by hydrolysis, furnished (-)-allo-norcoronamic acid with high ee, whilst diastereoselective Diels-Alder reaction of dienophile 13 and cyclopentadiene afforded, after double bond hydrogenation and hydrolysis, (-)-2-aminonorbornane-2-carboxylic acid. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00023-9

Tetrahedron: Asymmetry 11 (2000) 1051±1055
Chiral (Z)-a,b-didehydroamino acid derivatives from a new
chiral glycine equivalent with a 1,2,3,6-tetrahydropyrazin-2-one
structure: applications to the synthesis of 1-amino-
cyclopropanecarboxylic acids and bicyclic a-amino acids
Tomas Abellan, Carmen Najera* and Jose M. Sansano
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Departamento de Quõmica Organica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
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Received 21 December 1999; accepted 12 January 2000
Abstract
The new chiral glycine equivalent 9, easily obtained from (+)-a-aminoisovalerophenone and glycine, a€orded
chiral (Z)-a,b-didehydroamino acid (DDAA) derivatives 13 and 14 with a 1,2,3,6-tetrahydropyrazin-2-one
structure. Compounds 13 and 14 were synthesised by reaction of 9 with Eschenmoser's salt and by condensation
reactions with aldehydes or acetone under PTC conditions, respectively. The diastereoselective cyclopropanation
of 14, followed by hydrolysis, furnished ( )-allo-norcoronamic acid with high ee, whilst diastereoselective
Diels±Alder reaction of dienophile 13 and cyclopentadiene a€orded, after double bond hydrogenation and
hydrolysis, ( )-2-aminonorbornane-2-carboxylic acid. # 2000 Elsevier Science Ltd. All rights reserved.
a,b-Didehydroamino acids (DDAAs) are conformationally constrained non-proteinogenic amino
acids. As components of biologically natural peptides with potent antimicrobial and phytotoxic
activities, they also restrict the conformation and enhance the resistance to enzymatic and chemical
degradation.1 DDAAs are also important building blocks for the synthesis of biologically active
cyclic amino acids such as 1-aminocyclopropanecarboxylic acids (ACCs) and bicyclic a-amino
acids. ACCs are biosynthetic precursors of plant hormones, act as enzyme inhibitors and play an
important role in the regulation of enzymatic processes in plants.2 These cyclic amino acids, also
called 2,3-methanoamino acids, are mainly obtained from chiral DDAA derivatives such as 1±6 by
cyclopropanation reactions, through a 1,3-dipolar cycloaddition reaction with diazomethane3a,4,5
and by Michael addition of sulfoxonium4,6a,b,7 or phosphonium ylides.8 The best diastereoselectivities
were achieved when sulfoxonium ylides reacted with enantiomerically pure (E)-2,4 (Z)-57 or (Z)-66a,b
DDAA oxazinone derivatives. On the other hand, bicyclic a-amino acids are interesting molecules
from the pharmaceutical and biological point of view. For instance, 2-aminonorbornane-2-carboxylic
* Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00023-9

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T. Abellan et al. / Tetrahedron: Asymmetry 11 (2000) 1051±1055
1052
acids inhibit the transport of non-polar amino acids across cell membranes, act as an insulin-
releasing factor and inhibit the ¯avoprotein amino acid oxidases.9 For their diastereoselective
preparation chiral a-alkylideneoxazolidinones 110 (and related structures) and chiral a-alkylidene-
oxazinone 66b,c have been used as dienophiles in a non-catalysed process, while acyclic
didehydroalanine derivatives,11 as well as chiral and non-chiral oxazolones,12 have been tested
under a catalysed cycloaddition reaction.
Direct syntheses of cyclic chiral (E)- or (Z)-DDAA derivatives 1±5 have been achieved by
condensation of their corresponding glycine enolates with aldehydes under strong basic condi-
tions and very low temperatures (for compounds 313 and 53,7), by Horner±Wadsworth±Emmons
ole®nation (for products 114 and 24) or by chemical transformations of (Z)-alkylideneoxazolones
(for compound 45). Milder reaction conditions (PTC, K2CO3 and acetonitrile at room tempera-
ture) have recently been used by our group for the synthesis of oxazinone derivatives 6.6a,b
However, moderate yields have been obtained due to the sensitivity shown by these DDAA
derivatives to acidic or basic aqueous media and silica gel chromatography.
According to this experimental fact, and considering the similar chemical behaviour reported
between oxazinone 715 and tetrahydropyrazin-2-one 8,16 we have prepared a new chiral glycine
template N-Boc-(S)-6-isopropyl-5-phenyl-1,2,3,6-terahydropyrazin-2-one 9 for the asymmetric
synthesis of novel chiral (Z)-DDAA derivatives by a Knoevenagel-type condensation under mild
reaction conditions. In addition, the diastereoselectivity of cyclopropanation and Diels±Alder
reaction with sulfoxonium ylides and cyclopentadiene, respectively, was also studied.
The starting N-Boc protected pyrazin-2-one 9 was prepared following the same methodology
previously described for the synthesis of compound 8.16 Chiral auxiliary a-aminoketone hydro-
chloride 10,17,18 obtained in 70% overall yield from (S)-valine, underwent N-acylation with the
N-Boc-glycine pivalic acid mixed anhydride obtaining amide 11 in 97% yield. After deprotection
in acidic media and cyclisation using a saturated aqueous solution of potassium carbonate, pyr-
azinone 12 was obtained in 90% yield. Final N-Boc protection of heterocycle 12 was carried out
with di-tert-butyl dicarbonate at 0ꢀC in the presence of catalytic amounts of 4-N,N-dimethyl-
aminopyridine (DMAP) furnishing pyrazin-2-one 9 in 89% yield (Scheme 1).
The condensation reaction of 9 with aldehydes (2.5 equiv.) and acetone (2.5 equiv.) took place
under solid±liquid phase transfer catalysis with K2CO3 (3 equiv.) and tetra-n-butylammonium
bromide (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 Na2CO3 and K2CO3 was required in order to avoid partial isomerisation of double bonds to
all endo conjugated position (Table 1, entry 5). DDAA derivatives 14 were obtained in >98% de
and as single (Z)-diastereoisomers in good yields after chromatographic puri®cation without any

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1053
Scheme 1.
signi®cant decomposition. It is noticeable that the condensation reaction of 9 with acetone took
place in 51% yield (Table 1, entry 6). To date, the condensation reaction of the precursor of 5
with acetone in 10% yield is the only example of condensation reaction with ketones reported in the
literature.3a For the preparation of the corresponding didehydroalanine derivative, Eschenmoser's
salt (2 equiv.) reacted with 9 in dichloromethane at room temperature for 4 h (Scheme 2 and Table 1,
entry 1) a€ording directly dehydroalanine derivative 13.
Scheme 2.
Table 1
Synthesis of chiral (Z)-a,b-didehydroamino acid derivatives 13 and 14
Con®gurational assignments were made from 1H NMR data (300 MHz, CDCl3) obtained from
crude reaction product. 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, C±H coupling constants
between ole®nic protons and carbonylic carbon (close to 5 Hz) in proton-coupled 13C NMR are
consistent with the (Z)-con®guration.3b,6 Several attempts were made using stronger bases (BunLi,
LHMDS, LDA, ButOLi, ButOK) at lower temperatures in order to invert the stereochemistry of
alkene 14, but almost 1:1 mixtures of diastereoisomers were achieved in all cases.

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T. Abellan et al. / Tetrahedron: Asymmetry 11 (2000) 1051±1055
1054
The reaction of 14a and 14b with Corey's dimethylsulfoxonium methylide,19,20 which was
generated in situ from trimethylsulfoxonium iodide and sodium hydride in DMSO, took place in
1 h at room temperature a€ording spiro-compounds as 11:1 and 23:1 mixtures of diastereoisomers,
1
respectively, determined by GC, H and 13C NMR spectroscopy (Scheme 3). Pure major isomers
15a and 15b were isolated after ¯ash chromatography in 70% and 79% yields, respectively. When
using DMF instead of DMSO as solvent at 20ꢀC an improvement of the diastereoselectivity was
observed. Product 15a was submitted to acidic hydrolysis (3 M hydrochloric acid, 150ꢀC for 4 d) to
provide ( )-allo-norcoronamic acid ( )-16a6a,b in enantiomerically pure form (>98% ee) in 24%
yield (Scheme 3).
Scheme 3.
When DDAA derivative 13 was tested as dienophile in Diels±Alder cycloaddition reaction with
cyclopentadiene at room temperature for 3 h, the adduct 17 was isolated in 42% yield after ¯ash
chromatography as a single diastereoisomer. The probable structure of endo-adduct 1721 could
not be determined by X-ray di€raction analysis. Its stereochemistry was con®rmed after genera-
tion of bicyclic a-amino acid ( )-18,6b,c which was isolated, after hydrogenation (Pd/C in EtOAc
at rt) followed by acidic hydrolysis, in 84% overall yields and >98% ee (Scheme 4).
Scheme 4.
In conclusion, the synthesis of a new chiral glycine template 9 and its DDAA derivatives with
pyrazinone structure have been prepared in better yields than related oxazinones 6. The obtained
enantiomerically pure (Z)-DDAA derivatives from aldehydes were diastereoselectively cyclo-
propanated with Corey's ylide with better de and higher yields than the oxazinones 6. Hydrolysis
of spiro-compound 15a a€orded ( )-allo-norcoronamic acid. Diels±Alder reaction with cyclo-
pentadiene took place with endo-selectivity under similar conditions as oxazinones to give ( )-2-
aminonorbornane-2-carboxylic acid. Further work to exploit the synthetic uses of these hetero-
cycles is underway.
Acknowledgements
We thank the Direccion General de Investigacion Cientõ®ca y Tecnica (DGICYT) of the
Spanish Ministerio de Educacion y Cultura (M.E.C.) (PB97-0123). J.M.S. thanks the M.E.C. for

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T. Abellan et al. / Tetrahedron: Asymmetry 11 (2000) 1051±1055
1055
a contract under the program Acciones para la Incorporacion a Espana de Doctores y Tecnologos.
T.A. also thanks Lilly for a grant.
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