Regio- and diastereoselective synthesis of cyclic amino esters

Article abstract of DOI:10.1016/S0040-4039(00)02217-6

Several cyclic amino esters have been prepared regio- and diastereoselectively depending on the electrophile (cis or trans alkene) and its leaving group.

Full text of DOI:10.1016/S0040-4039(00)02217-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 991–992
Regio- and diastereoselective synthesis of cyclic amino esters
Kyung-Ho Park, Thomas M. Kurth, Marilyn M. Olmstead and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
Received 25 October 2000; accepted 22 November 2000
Abstract—Several cyclic amino esters have been prepared regio- and diastereoselectively depending on the electrophile (cis or trans
alkene) and its leaving group. © 2001 Published by Elsevier Science Ltd.
1-Amino cyclopropane (5) and 1-amino cyclopentene
(6) carboxylate ester derivatives are key precursors to
2,3-methanoamino acids1 and biologically important
excitatory amino acids,2 respectively. Indeed, significant
effort has been applied to the synthesis of cyclopropane
amino acid derivatives like 53—both because of their
abundance in nature4 and because of their interesting
biological properties.5 A previous study from our lab
required cyclopentene amino acid 6 as starting material
and, in that work, we observed that alkylation of 1 with
2a (X=Cl) gave only 4 with no trace of the potential
cyclopropane amino acid side product (3, R=H; Table
1, entry 1).6 We have since found, and report here, that
alkylation of 1 with altered bis-electrophile 2 [modify-
ing ‘X’ (entry 2) and/or the olefin geometry (entries
3–5)] allows for control of which cyclic amino ester (i.e.
3 versus 4) is produced. In contrast, a related and
stepwise palladium(0)-mediated route to the cyano
analog of 3 from either cis- or trans-2 gives no cyclo-
pentene product (cyano analog of 4).3
Condensation of the hydrochloride salt of glycine ethyl
ester with 4-bromobenzaldehyde delivers Schiff base7 1
(5 mmol scale, 95%) and activates the methylene moiety
of glycine for C-alkylation. Base treatment of 1 (excess
NaH in THF or THF/DMF 10:1) followed by addition
of bis-electrophile 2 results in bis-alkylation to the
protected amino esters 3 and/or 4 (3 mmol scale, :
80%). Subsequent hydrolysis of the labile imine with 1N
HCl followed by neutralization of the resulting ammo-
nium salt with 1N NaOH delivered cyclic amino esters
5 or 6 with good to excellent regioselectivity (i.e. 5
versus 6) and, in the case of 5, excellent diastereoselec-
tivity (Table 1). When cis-1,4-dichloro-2-butene (2a,
X=Cl) is employed as the alkylating agent, only
cyclopentene amino ester 6 is obtained (entry 1)—that
is, only direct SN2 displacement of chloride is operative
in the ring-closing alkylation step. On the other hand,
cis-1,4-dimesyl-2-butene8 (2a, X=OMs) delivered
cyclopropane 5 (R=H) as the major product together
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02217-6

992
K.-H. Park et al. / Tetrahedron Letters 42 (2001) 991–992
Table 1. Regio- (5 versus 6) and stereoselective (5: amine and vinyl moieties trans) cyclic amino ester synthesis
Entry
Alkylating agent
Product
Yielda (%)
Reaction conditions
1
2
3
4
5
2a (X=Cl)
2a (X=OMs)
2b (X=Cl, R=H)
2b (X=Cl, R=Me)
2b (X=Cl, R=Et)
6
67
60
43
25
20
THF, reflux
5 (R=H)/6 (2:1)
THF/DMF, rt
THF/DMF, rt
THF/DMF, rt
THF/DMF, rt
5
5
5
a Overall yield from Schiff base 1.
MgSO4, and concentrated under reduced pressure. The
residue was roughly purified by short column chro-
matography (silica-gel, presaturated with 10% Et3N in
hexane) to afford crude compound 3 (R=H), which
was treated with aqueous HCl (1N, 2 mL) for 20 min.
Ethyl acetate (10 mL) and water (10 mL) were added to
the reaction mixture and the separated aqueous layer
was neutralized with 1N NaOH (3 mL) and extracted
with ethyl acetate. The combined organic layer was
dried over anhydrous MgSO4, and concentrated under
reduced pressure to give compound 5 (R=H) (0.12 g,
0.79 mmol, 43%) as a liquid. FTIR (thin film) 3381,
Figure 1. X-Ray crystal structure of 7.
1
3322, 2980, 1720 cm−1; H NMR (300 MHz, CDCl3) l
5.69 (ddd, 1H, J=17.4, 10.3, 10.3 Hz), 5.21 (dd, 1H,
J=17.4, 1.8 Hz), 5.03 (dd, 1H, J=10.3, 1.8 Hz), 4.21–
4.10 (m, 2H), 2.08 (s, 2H), 2.04–1.97 (m, 1H), 1.55 (dd,
1H, J=7.4, 4.7 Hz), 1.33 (dd, 1H, J=9.4, 4.7 Hz), 1.27
(t, 3H, 7.2 Hz); 13C NMR (75 MHz, CDCl3) l 173.8,
135.1, 116.3, 61.1, 42.5, 35.7, 23.1, 14.4.
with cyclopentene 6 [5 (R=H)/6=2:1; entry 2]. The
occurrence of 5 as the major product in this reaction
with the cis-alkene bis-mesylate electrophile can be
explained on the basis of the Hard/Soft-Acid/Base
theory.9
In an effort to achieve complete regioselectivity in 1“5,
we investigated the use of trans-1,4-dichloro-2-butene
derivatives (2b, R=H, Me, Et) as the bis-alkylating
agent reasoning that a trans-configured alkene would
geometrically preclude formation of 6. As anticipated,
cyclopropane amino ester 5 was obtained exclusively
with trans-2b bis-electrophiles (entries 3, 4 and 5). It is
interesting to note that only one diastereomer (amine
and vinyl moieties are trans) is obtained in each of
these reactions, implying that a syn alkenyl and car-
boalkoxy relationship is sterically favored in the SN%
cyclization. X-Ray crystallographic analysis of urea 7,
prepared from 4-bromophenylisocyanate and cyclo-
propane amino ester 5 (R=H), verified the relative
stereochemistry in these useful amino cyclopropane car-
boxylate ester derivatives (Fig. 1).10
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