Asymmetric synthesis of substituted 1-aminocyclopropane-1-carboxylic acids from a new chiral glycine equivalent with 3,6-dihydro-2H-1,4-oxazin-2- one structure

Article abstract of DOI:10.1016/S0957-4166(98)00244-4

Condensation of the new chiral glycine equivalent 10 with aldehydes at room temperature in the presence of K₂CO₃ under solid-liquid phase- transfer-catalysed conditions afforded stereoselectively new chiral (Z)- α,β-didehydroamino ac

Full text of DOI:10.1016/S0957-4166(98)00244-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2223–2227
Asymmetric synthesis of substituted 1-aminocyclopropane-
1-carboxylic acids from a new chiral glycine equivalent with
3,6-dihydro-2H-1,4-oxazin-2-one structure †
Rafael Chinchilla,a Larry R. Falvello,b,‡ Nuria Galindo a and Carmen Nájera a,∗
aDepartamento de Química Orgánica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
bDepartamento de Química Inorgánica, Instituto de Ciencias de los Materiales de Aragón, Facultad de Ciencias,
Universidad de Zaragoza-CSIC, 50009, Zaragoza, Spain
Received 28 May 1998; accepted 16 June 1998
Abstract
Condensation of the new chiral glycine equivalent 10 with aldehydes at room temperature in the presence
of K2CO3 under solid–liquid phase-transfer-catalysed conditions afforded stereoselectively new chiral (Z)-α,β-
didehydroamino acid (DDAA) derivatives with oxazinone structure 14. These systems have been used in diastereo-
selective cyclopropanation reactions for the synthesis of enantiomerically pure 1-aminocyclopropanecarboxylic
acids (ACCs) such as (−)-allo-norcoronamic and (−)-allo-coronamic acids. © 1998 Elsevier Science Ltd. All
rights reserved.
1-Aminocyclopropane-1-carboxylic acids (ACCs), also referred to as 2,3-methanoamino acids, con-
stitute an important family of conformationally constrained α-amino acids because of their biological
activity and as components of peptides, being present in nature in the unbound form or as simple
dipeptides.1 The parent compound (ACC, 1), a biosynthetic precursor of the plant hormone ethylene2
and ammonia and 2-ketobutyrate in Pseudomonas,3 is a non-chiral compound but other important ACCs
have two stereogenic centers with cis and trans (or Z and E) relative configuration. Some representative
naturally occurring ACCs are coronamic acid 2b, an inhibitor of certain ACC-metabolizing enzymes
including ethylene forming enzyme (EFE) (isolated by hydrolysis of the vivotoxin coronatin)1b,2 and
also allo-norcoronamic 3a and allo-coronamic 3b acids, which play an important role in the control of
enzymatic processes for plant growth and fruit ripening.1b,3,4
∗
†
‡
Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
Dedicated to the memory of Professor Antonino Fava.
To whom the correspondence on X-ray structure should be addressed.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00244-4

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The synthetic challenge in the preparation of ACCs lies in controlling the relative and absolute
stereochemistry in the cyclopropane ring. Some developed syntheses are based on naturally occurring
chirons by several step procedures.1b,5 However, the most direct synthetic strategy for creating the two
required stereogenic centers involves the transformation of a chiral glycine equivalent into chiral α,β-
didehydroamino acid (DDAA) derivatives,6 followed by a diastereoselective cyclopropanation reaction.
The preparation of chiral DDAA derivatives also requires the control of the stereochemistry of the
carbon–carbon double bond, which has been achieved: (a) by direct condensation with aldehydes under
strong basic conditions (ButOK) and a very low reaction temperature for the pinanone derivative 47a–c
and diketopiperazine 57d giving Z- and E-derivatives respectively with low diastereoselectivity; (b)
by Horner–Wadsworth–Emmons olefination of phosphonate derivatives for imidazolidinones 67e,f and
oxazinones 7;7g and (c) by transformation of (Z)-alkylidenoxazolones into chiral diketopiperazines 8.7h
The cyclopropanation of some of these DDAA derivatives has been carried out by: (a) 1,3-dipolar
addition of diazomethane with low diastereoselectivity in the case of compounds 4,7a,b 7,7g and 8;7h
and (b) Michael addition of sulfoxonium7c,g or phosphonium ylides8 in the case of 47c and 7,7g or 68
(X=O), respectively.
We have previously reported the synthesis of a new iminic alanine chiral template with 3,6-dihydro-
2H-1,4-oxazin-2-one structure 9.9 This heterocycle can be alkylated with high diastereoselectivity
at room temperature either under solid–liquid phase-transfer catalysis using K2CO3 as base, or by
palladium-catalysis under neutral conditions allowing after hydrolysis the asymmetric synthesis of (S)-α-
methyl-α-amino acids. In this communication we describe the preparation of enantiomerically pure 1,4-
oxazin-2-one 10, a new glycine equivalent for the asymmetric synthesis of ACCs after diastereoselective
cyclopropanation of new chiral (Z)-DDAA derivatives prepared by a Knoevenagel-type condensation
under very mild reaction conditions.
Starting oxazinone 10 was prepared in 56% overall yield by 1,3-dicyclohexylcarbodiimide (DCC)-
mediated reaction of (S)-2-hydroxyisovalerophenone 1210 with N-Boc-glycine to give ester 13, followed
by deprotection of the Boc group and subsequent treatment with a CH2Cl2 solution of Me3N. The
synthesis of the chiral auxiliary 12 was carried out in 53% overall yield from (S)-2-hydroxyisovaleric
acid11 11 by amidation with dimethylamine hydrochloride under DCC-1-hydroxy-1H-benzotriazole
(HOBt) conditions,12 followed by addition of 3 equiv. of phenylmagnesium bromide (Scheme 1).
The reaction of oxazinone 10 with aldehydes was carried out under solid–liquid phase transfer catalysis

R. Chinchilla et al. / Tetrahedron: Asymmetry 9 (1998) 2223–2227
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Scheme 1.
Table 1
Synthesis of chiral α,β-didehydroamino acid derivatives 14
in the presence of K2CO3 (3 equiv.) and tetrabutylammonium bromide (TBAB, 0.1 equiv.) in CH3CN
at room temperature. The (Z)-DDAA derivatives 14 were thus stereoselectively obtained in >96%
diastereomeric excess (1H NMR, 300 MHz) independently of the substitution on the aldehyde, the pure
Z-isomers being isolated after flash chromatography (see Scheme 1 and Table 1).
1
Configurational assignments were made from H NMR spectra (300 MHz, CDCl3) of crude Z/E
diastereomeric 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 are typical of a Z-configuration.7b The
stereochemical assignment was unequivocally established for 14a by X-ray crystallographic analysis13
(Fig. 1).
Treatment of 14a and 14b with Corey’s dimethylsulfoxonium methylide,14 prepared with NaH in
DMF, over 1 h at room temperature afforded ca. 9:1 mixture of diastereomers (determined by GC and 1H
NMR) the major ones 15a and 15b being isolated after flash chromatography (silica gel) in 52 and 63%
yield, respectively (Scheme 2). When the cyclopropanation reaction was carried out at −55°C in DMF
similar diastereoselectivities were observed.
This methodology was applied to the synthesis of (−)-allo-norcoronamic (−)-3a and (−)-allo-
coronamic (−)-3b acids. Thus, spirocyclic compounds 15 were hydrolysed with 6 N HCl at 150°C
(pressure tube) for 1 day and, after treatment of the corresponding hydrochlorides with propylene oxide,
the free amino acids (−)-3a15 and (−)-3b16 were obtained in 60 and 67% yield, respectively (Scheme 2).
In conclusion, we have found that glycine-derived oxazinone 10 is a good precursor for the stereo-
selective synthesis of new enantiomerically pure (Z)-DDAA derivatives by simple condensation with
aldehydes under solid–liquid phase-transfer catalysis at room temperature. These DDAA derivatives can

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R. Chinchilla et al. / Tetrahedron: Asymmetry 9 (1998) 2223–2227
Fig. 1. X-Ray crystal structure of 14a
Scheme 2.
be easily cyclopropanated affording, after hydrolysis, enantiomerically pure ACCs. Studies about further
synthetic uses of these new chiral DDAA derivatives are underway.
Acknowledgements
We thank the Dirección General de Investigación Científica y Técnica (DGICYT) of the Spanish
Ministerio de Educación y Cultura (MEC) (PB94-1515 and PB95-0792) for financial support. N. G.
thanks MEC for a grant.
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