Regio- and stereoselective heck arylations of N-carbomethoxy-L-3- dehydroproline methyl ester with arenediazonium salts. Total synthesis of neuroexcitatory aryl kainoids

Article abstract of DOI:10.1021/ol070980t

The Heck arylation of N-carbomethoxy-L-3-dehydroproline methyl ester with arenediazonium tetrafluoroborates produced chiral 4-aryldehydroproline derivatives in moderate to good yields in a highly regio- and stereocontrolled fashion. A rationale for the un

Full text of DOI:10.1021/ol070980t

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2815-2818
Regio- and Stereoselective Heck
Arylations of N-Carbomethoxy-
L
-
3-Dehydroproline Methyl Ester with
Arenediazonium Salts. Total Synthesis
of Neuroexcitatory Aryl Kainoids
Kezia Peixoto da Silva, Marla Narciso Godoi, and Carlos Roque Duarte Correia*
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP, C.P. 6154,
13084-971, Campinas, Sa˜o Paulo, Brazil
roque@iqm.unicamp.br
Received April 30, 2007
ABSTRACT
The Heck arylation of N-carbomethoxy-L-3-dehydroproline methyl ester with arenediazonium tetrafluoroborates produced chiral 4-aryldehy-
droproline derivatives in moderate to good yields in a highly regio- and stereocontrolled fashion. A rationale for the unexpected high
regioselectivity is provided using Deeth’s model. Heck adduct 15 (G
efficient routes.
)
o-CH3O) was converted into several aryl kainoids using concise and
The C-C coupling reactions promoted by palladium are
pivotal constructive methodologies in modern organic syn-
thesis.1 The Heck arylation holds a prominent position in
synthesis due to its exceptional versatility.2 Of the many
electrophiles available, the arenediazonium salts are probably
the least explored ones in spite of some synthetic advantages.3
Recently, we have shown that the Heck arylation of
3-pyrrolines using arenediazonium salts opens up opportuni-
ties in synthesis. For example, the synthesis of Rolipram, a
selective phosphodiesterase IV inhibitor, was synthesized in
66% overall yield in three steps from 3-pyrroline in multi-
gram scale.4
Encouraged by these results, we decided to extend this
methodology to the versatile building block L-3-dehydro-
proline. However, to the best of our knowledge, there was
no previous report for the Heck reaction on this nonactivated
olefin. The closest precedents we have found were the Heck
arylation of aminobutenols reported by Crisp and the recent
intramolecular Heck reaction of 3-dehydroprolinol reported
by Evans.5
(1) (a) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.: Wiley: Hoboken, NJ, 2002. (b) Palladium Reagents and
Catalysis; Tsuji, J., Ed.; Wiley: Chichester, UK, 1995.
(2) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61,
11771. (b) Tietze, L.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453.
(3) For a review of Pd-catalyzed cross-coupling reactions using diazonium
salts, see: Roglans, A.; Pla-Quintana, A.; Moreno-Man˜as, M. Chem. ReV.
2006, 106, 4622.
(4) Garcia, A. L. L.; Carpes, M. J. S.; Montes de Oca, A. C. B.; Santos,
M. A. G.; Santana, C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70, 1050.
10.1021/ol070980t CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/23/2007

Therefore, our objectives from the onset of this study were
the evaluation of this Heck reaction as well as from the regio-
and stereocontrol of the arylation process. On the synthetic
standpoint, the Heck protocol would allow access to 4-aryl-
prolines 1 (organic catalysts) and to complex aryl kainoids
(Figure 1).6
Table 1. Synthesis of 4-Arylprolines from Dehydroproline 5a
time
(h)d
overall
yield (%)e
entry
G
protocol
yieldb
1
2
3
4
5
6
7
8
9
4-OMe
2-OMe
4-OMe
2-OMe
4-Cl
4-Br
4-F
4-NO2
4-NO2
3,4-Cl2
3-NO2
A
A
B
B
B
B
B
A
B
B
B
nd (6a)c
nd (7a)c
86 (6b)
92 (7b)
95 (8b)
70 (9b)
55 (10b)
35 (11a)
62 (11b)
61 (12b)
57 (13b)
4
4
18
12
4
5
18
4
60 (14)
65 (15)
61 (14)
82 (15)
85 (16)
45 (17)
0f (18)
10g (19)
15g (19)
25 (20)
38 (21)
4
3.5
5.5
10
11
a Reaction conditions. Protocol A: step 1: ArN2BF4, Pd(OAc)2 (10 mol
%), CH3CN/H2O/AcOH (6/3/1), 60 °C, 3-4 h; step 2: 2,6-lutidine, TFAA,
toluene, 0 °C to rt, then reflux. Protocol B: step 1: ArN2BF4, Pd(OAc)2
(10 mol %), CH3OH, reflux, 4-18 h; step 2: NH4Cl, 120-150 °C. b Yields
refer to a mixture of diastereomers after purification. The letter refers to
the type of R group in the Heck adducts, a: R ) H; b: R ) CH3. c Yields
for the Heck step not determined. Adducts were purified and submitted to
dehydration. d Heck step only. e Yields for the 2-dehydroprolines 14-21
after purification. f Low conversion of 10b, together with decomposition
products. g Low conversion of 11b.
Figure 1. Examples of kainoid compounds.
Aryl kainoid 3 displays potent activity as a neuroexcitatory
neurotransmitter related to kainic acid 4, an important gluta-
mate derivative often used as a pharmacological probe.7
Acromelic acid 2 and aryl kainoid 3 display neurotoxic
activity several times stronger than that of the kainic acid
itself.6a-c
We began with the arylation of N-carbomethoxy-L-3-dehy-
droproline methyl ester 5 using several arenediazonium salts
to test the feasibility of the intended protocol. Dehydroproline
5 was prepared in multigram scale from trans-4-hydroxy-
proline as described by Wong (61% yield over four steps).8
Bearing in mind our previous results with 3-pyrroline, these
reactions were devised as a two-step process (Table 1).4 The
first step consisted of the Heck arylation of dehydroproline
5 to the corresponding 4-aryl-2-hydroxy- or the 4-aryl-2-
methoxyprolines (adducts 6a to 13b, Table 1). The second
step encompassed the dehydration/methanol elimination to
reconstruct the primary Heck adducts 14-21.
Surprisingly, the conditions developed for the arylation
of 3-pyrroline (2 mol % of Pd(OAc)2 at 30 °C)4 proved
noneffective, leading to the recovery of dehydroproline 5
almost quantitatively. However, Heck arylations were ef-
fective at 60 °C, requiring an increase in the catalyst loading
(10 mol %). After much experimentation, we found out that
the Heck arylation of dehydroproline 5 can be carried out
effectively with a variety of arenediazonium salts to provide
the 4-aryl-2-hydroxy- or 4-aryl-2-methoxyproline derivatives
(protocols A and B, Table 1). Interestingly, the use of base
inhibits Heck arylation. The Heck reaction employing
protocol A (CH3CN/H2O) works best in the presence of
catalytic amounts of acetic acid to furnish the corresponding
lactamols. Protocol B, employing methanol as solvent, was
the most effective, furnishing the diastereomeric Heck
addition products in higher yields and fewer side products.
In spite of its advantages, methanol elimination proved to
be a nontrivial step, due to some erratic results employing
Shono’s protocol9 (NH4Cl, 140-160 °C). Heck arylation
using a mixture of DMSO/H2O also seemed to be a viable
alternative, providing the expected lactamols in yields com-
parable to those obtained with CH3CN/H2O/AcOH. Attempts
to perform the Heck arylation in anhydrous CH3CN failed
or resulted in very low yields of the desired Heck adducts.
The Heck addition products 2-hydroxyprolines 6a, 7a, and
11a were converted to the 4-aryl-2-dehydroprolines 14, 15,
(5) (a) Crisp, G. T.; Gebauer, M. G. Tetrahedron 1996, 52, 12465. (b)
Evans, P. J. Org. Chem. 2007, 72, 1830. Evans attempts to carry out Heck
arylation of a L-3-dehydroproline derivative yielded mainly 2-carboethoxy
pyrrole.
(6) (a) Maeda, K.; Kadama, T.; Tanaka, T.; Yoshiziemi, H.; Takemoto,
T.; Nomoto, K.; Fujita, T. Chem. Pharm. Bull. 1986, 34, 4892. (b) Shinozaki,
H.; Ishida, M.; Okamoto, T. Brain Res. 1986, 399, 395. (c) Ishida, M.;
Shinozaki, H. Brain Res. 1988, 474, 386. (d) For a review, consult: Parsons,
A. F. Tetrahedron 1996, 52, 4149.
(7) (a) Itadami, S.; Takai, S.; Tanigawa, C.; Hashimoto, K.; Shirahama,
H. Tetrahedron Lett. 2002, 43, 7777. (b) Ahmed, A.; Bragg, R. A.; Clayden,
J.; Tchabanenko, K. Tetrahedron Lett. 2001, 42, 3407. (c) Bragg, R. A.;
Clayden, J.; Bladon, M.; Ichihara, O. Tetrahedron Lett. 2001, 42, 3411.
(d) Maeda, H.; Selvakumar, N.; Kraus, G. A. Tetrahedron 1999, 55, 943.
(e) Maeda, H.; Kraus, G. A. J. Org. Chem. 1997, 62, 2314. (f) Baldwin, J.
E.; Fryer, A. M.; Spyvee, M. R.; Whitehead, R. C.; Wood, M. E.
Tetrahedron Lett. 1996, 37, 6923. (g) Hashimoto, K.; Shirahama, H.
Tetrahedron Lett. 1991, 32, 2625. (h) Hashimoto, K.; Horikawa, M.;
Shirahama, H. Tetrahedron Lett. 1990, 31, 7047.
(8) Lin, C.-C.; Shimazaki, M.; Heck, M.-P.; Aoki, S.; Wang, R.; Kimura,
T.; Ritzen, H.; Takayama, S.; Wu, S.-H.; Weitz-Schmidt, G.; Wong, C.-H.
J. Am. Chem. Soc. 1996, 118, 6826.
(9) Shono, T.; Matsumura, Y.; Inoue, K. J. Chem. Soc., Chem. Commun.
1983, 1169.
2816
Org. Lett., Vol. 9, No. 15, 2007

and 19 according to a protocol developed in our laboratory.10
These protocols provided the key 4-aryl-2-dehydroprolines
14-21 in overall yields ranging from 10 to 85% (Table 1).
Although some results still need optimization, several key
features of these Heck arylations are noteworthy: (a) The
protocols developed are base-free, and the arylations were
actually carried out under acidic conditions. (b) The capture
of the primary Heck adduct by water or methanol is
apparently beneficial as it prevents conversion of the Heck
products to the corresponding pyrroles. (c) Heck arylation
occurred in a highly regio- and stereoselective manner, as
single stereoisomeric 4-aryl-2-dehydroprolines 14-21 were
obtained in optically active form in all cases. The absolute
configuration at C-4 was assigned as S on mechanistic
grounds, which was confirmed upon completion of the total
synthesis of a known aryl kainoid 3. (d) The high regiose-
lectivity of the Heck arylation was unexpected since no clear
bias for the exclusive arylation at C-4 was obvious when
we initiated this study. (e) Heck arylations performed in
methanol provided the Heck adduct in all cases, in moderate
to excellent yields. (f) Heck arylations can be performed with
arenediazonium salts bearing electron-withdrawing (EWG)
or electron-donating substituents.
The 4-aryl-2-dehydroprolines 14-21 were envisioned as
precursors for new prolines and aryl kainoids. In particular,
the synthesis of the Heck aryl dehydroproline 15 (entries 2
and 4, Table 1) posed as a key starting material for the total
synthesis of the neurotoxic aryl kainoid 3. Additionally, the
synthesis of this aryl kainoid would be instrumental to
provide definitive evidence for the stereochemical assign-
ments made for the Heck arylations described above,
including its absolute stereochemistry.
We initiated the synthesis by preparing simpler aryl
kainoids. The Heck adduct 4-(o-methoxyphenyl)dehydro-
proline 15 was obtained in a multigram scale from dehy-
droproline 5 in 82% yield (entry 4, Table 1). Following the
protocol reported by Rubio and co-workers,14 the 2-dehy-
droproline 15 underwent a smooth Michael addition reaction
with sodium ethylmalonate to provide the all trans triester
22 in 79% yield (Scheme 1). Acidic hydrolysis (6 M HCl,
Scheme 1. Synthesis of the All trans Aryl Kainoid 23
The overall yields for some 4-aryl-2-dehydroprolines were
hampered due to experimental difficulties in performing
methanol elimination using Shono’s conditions (entries 7-9,
Table 1).11
Although rationalization for the high stereoselectivity is
straightforward, the reasons for the high regioselectivity are
not. According to Deeth, the regiochemistry of the Heck
reaction of monosubstituted alkenes is controlled mainly by
the electronic nature of the double bond.12 We hypothesize
that, in analogy to Deeth’s proposition, the regioselectivity
is controlled by the electronic nature of the carbamate and
carboalkoxy groups located at C-2. Both groups would act
in synergy having an electronic influence similar to that
displayed by a single EWG directly attached to the double
bond.13 A model for such putative TS is presented in Figure
2. The EWGs located at C-2 probably impart a negative
110 °C, 72 h) of the triester 22 followed by in situ
decarboxylation and N-deprotection afforded the all trans
(allo) aryl kainoid 23 in 61% overall yield. The trans
relationship between H-2 and H-3 was secured on the basis
of the chemical shift for H-2 at 4.08 ppm, as described by
Shirahama.15
To obtain the C-3,C-4 cis configuration, we once again
adopted a strategy similar to that reported by Rubio.14
Deprotonation of intermediate 22 with LHMDS at 0 °C
followed by addition of phenylselenyl bromide provided the
phenylselenylated triester 24 in 72% yield (Scheme 2).
Standard oxidative deselenylation of 24 with hydrogen
peroxide in THF at 0 °C provided the desired tetrasubstituted
unsaturated triester intermediate 25, which proved unstable
during purification. Therefore, to avoid losses, the intermedi-
Figure 2. Rationale for the regioselectivity.
selectivity index (Ω)12 to the system, favoring formation of
the linear adduct (pathway b, arylation at C-4).
(14) (a) Ezquerra, J.; Escribano, A.; Rubio, A.; Remuin˜a´n, M. J.; Vaquero,
J. J. Tetrahedron: Asymmetry 1996, 7, 2613. (b) Ezquerra, J.; Escribano,
A.; Rubio, A.; Remuin˜a´n, M. J.; Vaquero, J. J. Tetrahedron Lett. 1995, 36,
6149.
(10) Oliveira, D. F.; Miranda, P. C. L.; Correia, C. R. D. J. Org. Chem.
1999, 64, 6446.
(11) At present, reaction conditions were optimized only for arenedia-
zonium containing the p-OMe, o-OMe, and p-Cl.
(12) Deeth, R. J.; Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004,
126, 7144.
(13) This assumption is precedented in the work of Deeth and co-workers
(ref 12). It is also conceivable that such a model would explain the results
obtained by Crisp and Evans (ref 5).
(15) H-2 chemical shift for kainate 23 appears at δ 4.08 (d, 3J ) 7.8
Hz), suggesting a C-2, C-3 trans relationship, as described by Shirahama
(ref 6b). The stereochemistry of the substituents at C-3 and C-4 can be
established by the empirical rules proposed by Baldwin and Shirahama:
(a) Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J. J. Org. Chem. 2001, 66,
2597. (b) Hashimoto, K.; Konno, K.; Shirahama, H. J. Org. Chem. 1996,
61, 4685.
Org. Lett., Vol. 9, No. 15, 2007
2817

derivatives 31 and 32, previously reported by Shirahama and
Kraus (Scheme 3). Kraus obtained both compounds in
Scheme 2. Synthesis of Aryl Kainoids 27-30
Scheme 3. Synthesis of Aryl Kainoids 31 and 32
racemic form,7d,e and Shirahama7h described the synthesis
of 32 as an advanced chiral intermediate in the total enan-
tioselective synthesis of the aryl kainoid 3. The spectroscopic
data obtained by us for compounds 31 and 32 were in full
agreement with those reported in the literature. However,
the critical specific rotation values for the aryl kainoids 31
and 32 were not available. Fortunately, the specific rotation
24
value for compound 32 ([R]D -36.6 (c 1.0, CHCl3)) was
kindly provided by Professor Kimiko Hashimoto (Kyoto
Pharmaceutical University) which compared well with the
24
value obtained by us ([R]D -38.6 (c 0.7, CHCl3)). These
data combined confirm the absolute stereochemistry for aryl
kainoid 30 as 2S, 3S, 4S, and also set the stereocenter for
the Heck adduct 15 as 4S. By analogy, the stereogenic center
present in 14-21 can also be attributed as 4S.
ate 25 was hydrogenated just after its preparation to provide
the expected all cis triester aryl kainoid 26 in 62% yield over
two steps. Gratifyingly, catalytic hydrogenation occurred with
high stereoselectivity.
In summary, the Heck arylation of dehydroproline 5 was
successfully accomplished employing several arenediazonium
tetrafluoroborates to produce the (4S)-aryl-2,3-dehydro-
prolines 14-21 in yields ranging from 10 to 85%. These
arylations were carried out with remarkable regio- and
stereocontrol. The regioselectivity observed for these aryla-
tions is a striking example of regiocontrol for a nonactivated
disubstituted alkene. The Heck adduct o-methoxyphenyl-2-
dehydroproline 15 was employed as key starting material in
the stereocontrolled total syntheses of the neurotoxic aryl
kainoids 27-32, in a few steps in good overall yields.
The triester intermediate 26 was then hydrolyzed under
controlled acidic conditions to furnish the dicarboxylic acid
27 in 80% yield. Removal of the N-carbomethoxy group of
27 was accomplished employing more harsh acidic hydroly-
sis (6 N HCl, reflux, 40 h) to provide the amino acid 28
(75% yield). Alternatively, diacid 27 can be esterified with
diazomethane to provide the all cis aryl kainoid diester 29
in 80% yield over two steps from 26.16 Epimerization at C-2
of diester 29 to the highly neuroexcitatory 2,3-trans-3,4-cis
aryl kainoid 30 proceeded smoothly under the protocol
developed by Mann.17 Deprotonation of aryl kainoid 29 with
KHMDS, followed by esterification with diazomethane of
the incipient diacid, produced the desired C-2, C-3 trans
epimer 30 in a moderate 60% yield.
Acknowledgment. We thank FAPESP for financial
support, and CNPq and CAPES for fellowships. We are also
thankful to Dr. Katsuhiro Konno from Butanta˜ Institute,
Brazil, and Professor Kimiko Hashimoto, from Kyoto Pharm-
aceutical University, Japan, for their helpful assistance con-
cerning the specific rotation value for the aryl kainoid 32.
The N-carbomethoxy aryl kainoids 29 and 30 constitute
new compounds. Therefore, to confirm the stereochemical
assignments made along the synthesis, N-carbomethoxy aryl
kainoid 27 was converted to the known N-carbobenzyloxy
Supporting Information Available: General experimen-
tal procedures for the Heck arylations and characterization
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Attempts to perform hydrolysis under basic conditions led to a
mixture of the all cis diester with its C-2 epimer in a 1:1 ratio.
(17) Klotz, P.; Mann, A. Tetrahedron Lett. 2003, 44, 1927.
OL070980T
2818
Org. Lett., Vol. 9, No. 15, 2007