Synthesis of chiral and geometrically defined 5,5-diaryl-2-amino-4-pentenoates: Novel amino acid derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00353-7

A novel series of 5,5-diaryl-2-amino-4-pentenoates were synthesized. Chirally defined substrates were obtained efficiently using Oppolzer's sultam as a chiral auxiliary and a palladium-catalyzed stereoselective hydrostannylation.

Full text of DOI:10.1016/S0040-4039(01)00353-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2957–2960
Synthesis of chiral and geometrically defined
5,5-diaryl-2-amino-4-pentenoates: novel amino acid derivatives
Methvin Isaac,* Abdelmalik Slassi, Kathleen Da Silva and Tao Xin
NPS Allelix Corp., 6850 Goreway Drive, Mississauga, ON, Canada L4V 1V7
Received 27 January 2001; revised 23 February 2001; accepted 1 March 2001
Abstract—A novel series of 5,5-diaryl-2-amino-4-pentenoates were synthesized. Chirally defined substrates were obtained
efficiently using Oppolzer’s sultam as a chiral auxiliary and a palladium-catalyzed stereoselective hydrostannylation. © 2001
Elsevier Science Ltd. All rights reserved.
The 5,5-diaryl-2-amino-4-pentenoate series was devel-
oped as a novel class of biologically active molecules
targeted towards the recently cloned glycine reuptake
transport system, specifically the glycine transporter
type-2 (GlyT-2) system. This system is prevalent in the
central nervous system and is thought to be involved in
the treatment of pain and spasticity.1 Of particular
interest from this series is the sodium derivative of
E-2-amino-5-[2,4-difluorophenyl]-5-[4-isopropylphenyl]-
4-pentenoic acid (1), which was found to be a potent
GlyT-2 reuptake inhibitor (IC50=330 nM) as a racemic
mixture. Resolving the racemate indicated that the S-
enantiomer 2 was the active component of the mixture
with an IC50 of 150 nM.
Scheme 1. (a) Pd(PPh3)4, CuI, propargyl alcohol, Et3N; (b) Red-Al, I2, ether; (c) PBr3, CH2Cl2, 0°C.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00353-7

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We wish to report on the synthesis of 1, highlighting
the various regio- and stereoselective control elements
utilized.
An alternative route to 1 is illustrated in Scheme 3. The
propargyl bromide 7b, prepared according to Scheme 1,
was reacted with 8 giving the highly functionalized
intermediate 12. The palladium-catalyzed stereoselec-
tive hydrostannylation7 of 12 provided 13 in 55% yield,
which was subsequently treated with iodine to effect a
tin to iodine exchange to afford 14 (Scheme 3). The
vinyl iodide 13 was immediately treated with 2,4-
difluorobenzeneboronic acid to give the Suzuki-coupled
product 15. Deprotection of 15, followed by base-medi-
ated hydrolysis, provided 1.
2,4-Difluoroiodobenzene 3a was subjected to the Sono-
gashira coupling condition2 with propargyl alcohol giv-
ing the alcohol 4a (Scheme 1). Treatment of 4a with
Red-Al, followed by quenching with iodine, afforded 5a
in good yield and in a regio- and stereospecific man-
ner.3 The alcohol functionality of intermediate 4a was
then transformed cleanly into the corresponding bro-
mide 6 using phosphorus tribromide.4
To further determine the effect of the chirality on
activity, 1 was resolved using a chiral column of an
analytical HPLC and the resolved components were
separated (Fig. 1).8 The absolute stereochemistry of the
active enantiomer 2 was confirmed using chemical cor-
relation methods.9
The allyl bromide 6a was used in the allylation of 8,5
with LDA as base, to afford the versatile intermediate
9, which can be reacted with a variety of boronic acids
(Scheme 2). Compound 9 was then coupled to 4-iso-
propylbenzeneboronic acid under the Suzuki-coupling
conditions furnishing 10 in good yield. Trifluoroacetic
acid-mediated deprotection, followed by hydrolysis,
furnished 1 in good overall yield.6
Utilizing Oppolzer’s bornane-10,2-sultam as a chiral
auxiliary, treatment of the sultam-derived N-(diphenyl-
Scheme 2. (a) LDA, THF, HMPA, −78°C to rt; (b) Ar2-B(OH)2, Pd(PPh3)4, DME/Na2CO3, 110°C; (c) TFA, H2O, CH2Cl2, rt;
(d) 1N NaOH, MeOH.
Scheme 3. (a) 8, LDA, THF, HMPA, −78°C to rt; (b) Bu3SnH, PdCl2(PPh3)2, THF; (c) I2, CH2Cl2; (d) Ar1-B(OH)2, Pd(PPh3)4,
DME/Na2CO3, 110°C; (e) TFA, H2O, CH2Cl2, rt; (f) 1N NaOH, MeOH.

M. Isaac et al. / Tetrahedron Letters 42 (2001) 2957–2960
2959
Figure 1.
Scheme 4. (a) (i) LDA, THF, HMPA, −78°C, (ii) 7b, −78°C to rt; (b) Bu3SnH, PdCl2(PPh3)2, THF; (c) I2, CH2Cl2; (d)
Ar1-B(OH)2, Pd(PPh3)4, DME/Na2CO3, 110°C; (e) TFA, H2O, CH2Cl2, rt; (f) 2.5N LiOH, H2O/THF.

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M. Isaac et al. / Tetrahedron Letters 42 (2001) 2957–2960
methylene)glycinate 2010 with the activated organic bro-
mide 7b affords the monoalkylated intermediate 16
with high diastereoselectivity (only one isomer was
observed) (Scheme 4). Regioselective hydrostannation
of 15, followed by tin–iodine, afforded the intermediate
17, which was then subjected to Suzuki coupling, tri-
fluoroacetic acid-mediated deprotection, followed by
lithium hydroxide-mediated hydrolysis of the chiral
auxiliary, to give the lithium salt of 2 as the pure
S-enantiomer.
hedron Lett. 1975, 50, 4467.
3. Blanchette, M.; Malamas, M.; Nantz, M.; Roberts, J.;
Somfai, P.; Whritenour, D.; Masamune, S. J. Org. Chem.
1989, 54, 2817.
4. Schlosser, M.; Micheal, D.; Croft, S. Synthesis 1996, 591.
5. For the synthesis of 8 from glycine methylester hydro-
chloride and benzophenone imine, see: O’Donnell, M.;
Polt, R. J. Org. Chem. 1982, 47, 2663.
6. Spectral data for the sodium salt of 1 (off-white solid). 1H
NMR (300 MHz, CD3OD) l: 7.35 (m, 1H), 7.22 (d, 2H,
J=8.1 Hz), 7.10 (d, 2H, J=8.1 Hz), 6.88 (m, 2H), 5.95 (t,
1H, J=6.9 Hz), 3.59 (broad, m, 1H), 2.90 (m, 1H), 2.82
(m, 2H), 1.24 (d, 6H, J=7.0 Hz). HRMS (FAB) calcd for
In conclusion, we have successfully synthesized a novel
amino acid 1 from N-(diphenylmethylene)glycinate pre-
cursors. The synthesis was carried out in a highly regio-
and stereodefined fashion, as illustrated by the asym-
metric synthesis of 2. The key highlight of the synthetic
strategy is the palladium-catalyzed stereoselective
hydrostannylation of the highly functionalized interme-
diates affording products 1 and 2 in good overall yield.
C22H20F2NO2
346.16044.
[M−Na+2H]+:
346.16187.
Found:
7. Liron, F.; Le Garrec, P.; Alami, M. Synlett 1999, 2, 246.
8. The chiral purity was determined by HPLC using the
CHIROBIOTIC T™ (Astec) column purchased from
Chromatographic Specialties Inc. and ethanol/water
(80:20) as the mobile phase.
9. Lopez, A.; Pleixats, R. Tetrahedron: Asymmetry 1998, 9,
1967.
Acknowledgements
10.
The authors would like to thank Dr. Shawn Maddaford
for his valuable discussions and suggestions.
References
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N.; McCallum, K. Bioorg. Med. Chem. Lett. 2001, in
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