Novel stereocontrolled addition of allylmetal reagents to α-imino esters: Efficient synthesis of chiral tetrahydroquinoline derivatives

Article abstract of DOI:10.1021/jo020327d

To prepare in multigram scale new antagonists of the glycine binding site associated to the NMDA receptor, an efficient distereoselective route was set up. The addition of suitable allyltin reagents to chiral N-aryl α-imino esters (R-(+)-tert-butyl lactate used as chiral auxiliary), gave the corresponding α amino acid-type derivative in high chemical yield and optical purity. This allylation reaction represents a novel example of efficient long-range stereodifferentiation process. In the last part of the synthesis, a regioselective Heck-type cyclization reaction enabled preparation of the target tetrasubstituted exocycle and trisubtituted endocycle double bond derivatives.

Full text of DOI:10.1021/jo020327d

Novel Ster eocon tr olled Ad d ition of Allylm eta l Rea gen ts to r-Im in o
Ester s: Efficien t Syn th esis of Ch ir a l Tetr a h yd r oqu in olin e
Der iva tives†
Romano Di Fabio,* Giuseppe Alvaro,* Barbara Bertani, Daniele Donati, Simone Giacobbe,
Carla Marchioro, Carlotta Palma, and Sean M. Lynn§
Medicines Research Centre, GlaxoSmithKline S.p.A, Via Fleming 4, 37135 Verona, Italy
rdf26781@gsk.com
Received May 13, 2002
To prepare in multigram scale new antagonists of the glycine binding site associated to the NMDA
receptor, an efficient distereoselective route was set up. The addition of suitable allyltin reagents
to chiral N-aryl R-imino esters (R-(+)-tert-butyl lactate used as chiral auxiliary), gave the
corresponding R amino acid-type derivative in high chemical yield and optical purity. This allylation
reaction represents a novel example of efficient long-range stereodifferentiation process. In the
last part of the synthesis, a regioselective Heck-type cyclization reaction enabled preparation of
the target tetrasubstituted exocycle and trisubtituted endocycle double bond derivatives.
In tr od u ction
The modulation of the NMDA receptor1 by antagonists
acting at the glycine binding site is perceived as one of
the most promising biological strategies to identify ef-
fective antihyperalgesic agents able to manage chronic
pain,2 an area still associated with high unmet needs in
current medicine. This pathophysiological event occurs
when tissues and/or nerves are damaged (e.g. neoplastic
infiltration, inflammation, ischaemia), resulting in the
alteration of the physiological relationship existing be-
tween painful stimuli and somatosensory response.3 A
significant body of evidence supports the hypothesis that
the activation of the ion-channel associated with the
NMDA receptor is responsible for the abnormal entry of
Ca2+ to the postsynaptic neurones, massive depolariza-
tion4 and increased excitability of spinal cord neurons, a
phenomenon known as wind-up. This biochemical event
is associated with the onset of severe and prolonged pain
states (hyperalgesia/allodynia). Glycine antagonists, block-
ing the overactivation of the NMDA receptor and restor-
ing the baseline level of nociceptive transmission, should
be effective for the treatment of the chronic pain.5
F IGURE 1. Indole 2-carboxylates and THQ derivatives as
glycine antagonists.
The extensive exploration performed by our group in
this field allowed the identification of the indole-2-
carboxylate derivative GV196771A,6 shown in Figure 1.
Remarkably, in animal models of chronic pain this
compound was found to be highly effective in conditions
distinct from those of classical opioids.
* Corresponding author. Fax. 39-45-9218196.
† Dedicated to the memory of J ohn A.Winders.
§ GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire, UK SG1 2NY.
(1) The NMDA Receptor, 2nd ed.; Collingridge, G. L., Watkins, J .
C., Eds.; IRL Press: Oxford, England, 1994.
(2) (a) Woolf, C. J . Nature 1983, 306, 686. (b) Davies, S. N.; Lodge,
D. Brain Res. 1987, 424, 402. (c) Haley, J . E.; Sullivan, A. F.;
Dickenson, A. H. Brain Res. 1990, 518, 218. (d) Woolf, C. J .; Thompson,
S. W. N. Pain 1991, 44, 299. (e) Woolf, C. J . Pulm. Pharmacol. 1995,
8, 161. (f) Harris, J . A.; Corsi, M.; Quartaroli, M.; Arban, R.; Ben-
tivoglio, M. Neuroscience 1996, 74, 7. (g) Dickenson, A. H.; Chapman,
V.; Green, G. M. Gen. Pharmacol. 1997, 28, 633.
(3) J essel, T. M.; Kelly, D. D. Pain and Analgesia. In Principles of
Neural Science; Kandel, E. R., Schwartz, J . H., J essell, T. H., Eds.;
Appleton & Lange: 1991; pp 385-399.
(4) Dickenson, A. H.; Chapman, V.; Green, G. M. Gen. Pharmacol.
1997, 28, 633.
(5) For a review on the drugs currently used to treat chronic pain
see: Karlsten, R.; Gordh, T. Drugs Aging 1997, 11, 398.
(6) (a) Di Fabio, R.; Conti, N.; Corsi, M.; Donati, D.; Gastaldi, P.;
Gaviraghi, G.; Giacobbe, S.; Pentassuglia, G.; Quartaroli, M.; Ratti,
E.; Trist, D. G.; Ugolini, A. Drugs Fut. 2000, 25, 137. (b) Quartaroli,
M.; Carignani, C.; Dal Forno, G.; Mugnaini, M.; Ugolini, A.; Arban,
R.; Bettelini, L.; Maraia, G.; Belardetti, F.; Reggiani, A.; Trist, D. G.;
Ratti, E.; Di Fabio, R.; Corsi, M. J . Pharmacol. Exp. Ther. 1999, 1,
290. (c) Giacobbe, S. A.; Baraldi, D.; Di Fabio, R. Biorg. Med. Chem.
Lett. 1998, 8, 1689.
10.1021/jo020327d CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/19/2002
J . Org. Chem. 2002, 67, 7319-7328
7319

Di Fabio et al.
SCHEME 1. Retr osyn th etic Ap p r oa ch to th e THQ Sca ffold
Tetrahydroquinoline (THQ) derivatives 1 and 2, shown
in Figure 1, were identified during the drug discovery
program, as potential alternatives to GV196771A. To
prepare these compounds in multigram scale, an efficient
synthesis was set up in which the key steps are repre-
sented by (a) the stereocontrolled formation of the C-2 R
amino acid-type stereogenic center; (b) the Heck-type
cyclization reaction to give selectively the exo or the endo
derivatives of type 1 and 2. To that end, the addition of
allyltin derivatives to suitable N-aryl R-imino esters, in
which commercially available R-(+)-tert-butyl lactate was
used as chiral auxiliary, and the use of specific Heck-
type reaction conditions, respectively, enabled us to
overcome these synthetic issues. In particular, as far as
the allylation reaction is concerned, the presence of
lactate esters was crucial to achieve high diastereocon-
trol, opening novel perspectives in stereoselective addi-
tion reactions to R-iminoesters for the preparation of both
natural and unnatural amino acids.
Scheme 1. Considering the possibility of performing a
Wittig-type olefination reaction to introduce the R,â-
unsaturated N-phenyl γ-lactam moiety, followed by a
Heck-type cyclization,7 the sequential dissection of the
C4-5 exendo bond of compounds 1 and 2 and the double
bond of intermediate 6, respectively, seemed to be the
most appropriate strategy to attempt. Therefore, the
identification of an efficient synthetic procedure to pre-
pare in large scale the enantiomerically pure N-aryl
allylglycine derivative 8, was perceived as the most
urgent problem to solve. Among the different potential
approaches, it was speculated that the addition of an
allylmetal derivative, in the presence of a suitable Lewis
acid, to a chiral N-aryl aldimine of type 9, could afford
compound 8, as a mixture of diastereoisomers, hopefully
separable by chromatography.8 The degree of π-facial
diastereocontrol of the allylation reaction could depend
(7) (a) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley &
Sons Ltd: Chichester, 1995. (b) Heck, R. F. Palladium Reagents in
Organic Synthesis; Academic Press: London, 1985.
Resu lts a n d Discu ssion
(8) For the synthesis of a different series of racemic THQ analogues
identified within the glycine antagonists-stroke program, see: Di Fabio,
R.; Alvaro, G.; Bertani, B.; Giacobbe, S. Can. J . Chem. 2000, 6, 78.
The retrosynthetic analysis, proposed for the synthesis
of tetrahydroquinoline derivatives 1 and 2, is shown in
7320 J . Org. Chem., Vol. 67, No. 21, 2002

Addition of Allylmetal Reagents to R-Imino Esters
SCHEME 2. Allylm eta la tion Rea ction a
a
(a) Acryloyl chloride, DMAP, CH2Cl2, 0 °C then rt, 2 h, 88%; (b) OsO4, NaIO4, THF/H2O, 3:1, rt, 12 h, 100%; (c) i. toluene, reflux; ii.
5-chloro-2-iodoaniline, 100%; (d) TiCl4, CH2Cl2, -78 °C, 15 min then allyltributyltin -78 °C, 1 h, 90%.
on the nature of both the chiral auxiliary R* selected and
the kind of metal used.9 A key requirement in the choice
of R* was the need to deprotect that group under mild
reaction conditions, to avoid the potential racemization
of the R amino acid-type stereogenic center.10
analysis) was isolated in 90% total yield. Remarkably,
despite the unfavorable C1-4 relationship existing be-
tween the lactate stereogenic center and the aldimine
reaction center, a promising level of π-facial diastereo-
selection was observed.
From the synthesis of the tetrahydroquinoline deriva-
tives of type 3, shown in Figure 1, it was known that the
corresponding R-(+)-tert-butyl lactate ester derivative
(prepared from the corresponding racemic carboxylic acid
derivative by Mitsunobu reaction11 followed by chromato-
graphic separation of the diasteroisomers) could be
hydrolyzed, with LiOH in EtOH/H2O at room tempera-
ture for 1 h, to afford the pure enantiomer without
epimerization of the N-aryl R-amino acid stereogenic
center. On the basis of this observation, an attempt to
use R-(+)-tert-butyl lactate as chiral auxiliary in the
allylmetalation reaction was performed as shown in
Scheme 2. To prepare the chiral aldimine 14, the com-
mercially available R-(+)-tert-butyl lactate 11 was re-
acted with acryloyl choride in CH2Cl2 at 0 °C in the
presence of a catalytic amount of DMAP, to give the
intermediate 12 in high yield. The following oxidative
cleavage of the double bond, with OsO4 and NaIO4,
furnished the glyoxylate ester 13. This intermediate was
reacted overnight with 5-chloro-2-iodoaniline in refluxing
toluene, with azeotropic removal of water using a Dean-
Stark apparatus and in the presence of anhydrous
MgSO4, to furnish the desired aldimine derivative 14 in
quantitative yield, as a stable compound. When 14 was
dissolved in dry CH2Cl2 and reacted at -78 °C with an
excess of TiCl4 (1.1 equiv) and allyltributyltin (1.5 equiv),
an inseparable mixture by flash chromatography of
diastereoisomers 15a and 15b (ratio 80:20 by HPLC
To investigate further the stereoelectronic features of
the lactate ester responsible for the significant degree of
stereocontrol observed, an attempt was made to assign
the absolute configuration of the stereogenic center of the
major diastereoisomer. To that end, as shown in Scheme
3, the p-methoxyphenyl aldimine derivative 16, smoothly
prepared as described for the analogous intermediate 14,
was transformed into the methyl ester of R-(-)-norvaline.
This sequence is feasible due the possibility of deprotect-
ing the p-methoxyaryl moiety at the end of the synthetic
sequence to restore12 the desired R-amino acid derivative.
As expected, when reactive intermediate 16 was treated
with allyltributyltin and TiCl4 at -78 °C in CH2Cl2,
diastereoisomers 17a and 17b were isolated in the same
80:20 ratio previously observed from the allylation reac-
tion with the aldimine 14. The most abundant compound
17a , after purification by flash chromatography, was
transformed into the corresponding carboxy derivative
19 by sequential hydrogenation with Pd/C 10% in EtOH
at 4 atm followed by hydrolysis of the R-(+)-tert-butyl
lactate with LiOH in a 2:1 mixture of THF/H2O. This
intermediate was then reacted with TMSCHN2 to give
the corresponding methyl ester 20. The p-methoxy phenyl
group was removed by cerium ammonium nitrate in CH3-
CN-H2O 10:1 at -25 °C, to give the desired R-(-)-
norvaline methyl ester 21 in moderate yield, after
purification by flash chromatography. This compound
was found to be identical both in terms of chiral HPLC
and CZE analysis to authentic R-(-)-norvaline methyl
ester, readily prepared from the commercially available
amino acid. Therefore, from this correlation study it was
possible to conclude that the R-(+)-lactate ester was able
to induce, in the allylation reaction, the preferential
formation of a (R) stereogenic center.13
(9) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
(10) For a relevant example of the diastereoselective addition of
organometallic compounds to chiral R-imino esters, see: Yamamoto,
Y.; Ito, W. Tetrahedron 1988, 44, 5423. The use of the cited 8-(-)-
phenylmenthyl ester, as chiral auxiliary, was unsuccessful in our case,
due to the insurmountable difficulty to remove it at the end of the
synthesis, avoiding racemization of the C-2 stereogenic center in basic
medium (LiOH), or the extensive degradation of the THQ scaffold in
the presence of BCl3.
With the aim of optimizing further the diastereoselec-
tivity observed, this allylmetalation reaction was re-
(11) For two reviews on the Mitsunobu reaction, see: (a) Hughes,
D. L. Org. Prep. Proced. Int. 1996, 28, 127-164. (b) Dodge, J . A.; J ones,
S. A. Recent Res. Dev. Org. Chem. 1997, 1, 273-283.
(12) Hagiwara, E.; Fujii, A.; Sodeoka, M. J . Am. Chem. Soc. 1998,
120, 2474.
J . Org. Chem, Vol. 67, No. 21, 2002 7321

Di Fabio et al.
SCHEME 3. Deter m in a tion of th e Absolu te Ster eoch em istr ya
a
(a) 4-Methoxyaniline, toluene, reflux, 30 min; (b) TiCl4, CH2Cl2, -78 °C, 20 min, then allyltributyltin, 30 min, 80%; (c) Pd/C 10%,
EtOH, H2 (4 atm), 6 h, 96%; (d) LiOH, THF/H2O 2:1, rt, 66%; (e) trimethylsilyldiazomethane, rt, CH2Cl2/MeOH 1:1, 90%; (f) CAN, CH3CN/
H2O 8:1, -25 °C, 40 min, 45%.
TABLE 1. Allylm eta la tion Rea ction : In ter m olecu la r Ad d ition
entry
MLn or AH
M
solvent
T
ratioa 17a /17b
1
2
3
4
5
6
7
-
SnBu3
SnBu3
SnBu3
SnBu3
SnBu3
SnBu3
SnBu3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-78 °C
-78 °C
-78 °C
-78 °C
-78 °C
-78 °C
-78 °C
-
80:20
70:30
71:29
68:32
72:28
75:25
TiCl4
ZnI2
Sc(OTf)3
Yb(OTf)3
BF3‚Et2O
p-TsOH
a
Determined by HPLC.
peated on the aldimine 16 with different Lewis and
Bro¨ensted acids. As shown in Table 1, a similar degree
of diastereoselectivity was obtained independently of the
nature of the Lewis or Bro¨ensted acid used. In particular,
when p-TsOH or BF3‚Et2O (entries 7 and 6, respectively)
were used, the degree of diastereoselectivity did not
change significantly with respect to the reactions per-
formed in the presence of TiCl4, ZnI2, Sc(OTf)3, and Yb-
(OTf)3, (entries 2, 3, 4, and 5, respectively). On the basis
of these results, it was speculated that (a) the coordina-
tion or the protonation of the nitrogen of the R-iminoester
by the Lewis or Bro¨ensted acid is crucial to promote the
allylation reaction; (b) the presence of (R)-lactate ester
is responsible for the preferential attack of the allyl
moiety on Re face of the imine.14 As shown in Figure 2,
the level of induction observed can be accounted for by
an “open-chain” or “chelated” imine complex (in the latter
(13) This result was confirmed by NOE studies performed on the
cyclic diastereoisomers A and B. These compounds were smoothly
prepared from the 80:20 mixture of 17a and 17b by sequential
chemoselective hydrolysis of the tert-butyl ester group followed by
cyclization with EDC and HOBT in DMF at room temperature, and
finally separation by flash chromatography.
7322 J . Org. Chem., Vol. 67, No. 21, 2002

Addition of Allylmetal Reagents to R-Imino Esters
F IGURE 2. Allylmetalation reaction: proposed mechanism.
TABLE 2. Allylm eta la tion Rea ction : In tr a m olecu la r
Ad d ition
conversion after 2 h) and the diastereocontrol of the
reaction was completely lost (entry 4; 17a /17b, 48:52).
Conversely, remarkable results were obtained when
aldimine 16 was added, at 0 °C in THF, to a preformed
solution of allyliododichlorotin19 in THF (entry 5), to give
diastereoisomers 17a and 17b in a 93:7 ratio. The level
of stereocontrol achieved was even higher in CH2Cl2
(entry 6; 17a /17b, >98:2), but the conversion after 2 h
at -78 °C was very low. Finally, the best results were
achieved with allyltrichlorotin20 at -78 °C in CH2Cl2.
This reaction was complete after 15 min, affording 17a
as the only diasteroisomer (entry 7; 17a /17b, >98:2), in
77% total yield from 16 after purification by flash
chromatography.21
On the basis of the degree of diastereoselectivity
observed, this allylation reaction can be considered as a
novel example of an efficient long-range stereodifferen-
tiation process using, as chiral auxiliary, a cheap mol-
ecule belonging to the chiral pool, particularly useful,
therefore, for preparative purposes. The stereochemical
control achieved could be explained, as shown in Figure
2, in terms of an intramolecular-type addition reaction
via formation of a more rigid hexa-coordinated tin transi-
tion state complex (B), in which the COOR group of the
lactate is coordinated by tin.22
%
ratioa
conversiona/t 17a /17b
entry
MLn
M
solvent
T
1
2
3
4
5
6
7
-
MgCl
Zn(CH3)2 MgCl
THF
THF
THF
DMF
-78 °C
-
-
-78 °C 75/1 h
-78 °C 75/1 h
0 °C 50/2 h
28:72
67:33
48:52
93:7
-
-
-
-
-
ZnBr
SiCl3
SnICl2 THF
SnICl2 CH2Cl2 -78 °C 20/2 h
SnCl3 CH2Cl2 -78 °C 100/15 min
0 °C 70/2 h
>98:2
>98:2
a
Determined by HPLC
case the imine moiety could act both as a bidentate or
tridentate ligand), in which the nucleophilic attack occurs
preferentially anti to the COOR group of the lactate.15
According to this transition state model, when R-imi-
noester 16 was precomplexed with Zn(CH3)2 and then
reacted with allylmagnesium chloride (Table 2, entry 2),
an opposite induction was observed (17a /17b, 28:72).16
In this case, the Grignard reagent should be, in fact,
coordinated by the COOR group of the lactate with
preferential delivery of the allyl moiety to the Si face of
the imine.
To maximize the degree of diastereoselectivity, further
investigations were performed using zinc, silicon, and tin
allylmetals, this time without the addition of Lewis acids.
The results achieved are summarized in Table 2. The
diastereomeric ratio did not vary significantly with
respect to the reactions shown in Table 1 in the case of
allylzinc bromide (entry 3).17 When aldimine 16 was
treated at 0 °C in DMF with an equimolar amount of
allyltrichlorosilane,18 a slow reaction occurred (50%
The optimized allylation reaction was applied to the
synthesis of the target compounds 1 and 2. As shown in
Scheme 4, when allyltrichlorotin was reacted with the
aldimine 14, the desired allyl derivative 15 was obtained,
once again, as a single diastereoisomer in 90% yield in
two steps from 5-chloro-2-iodoaniline. Remarkably, the
(18) For the addition of allyltrichlorosilane to benzoylhydrazones,
see: Kobayashi, S.; Hirabayashi, R. J . Am. Chem. Soc. 1999, 121, 6942.
(19) (a) Alvaro, G.; Boga, C.; Savoia, D.; Umani-Ronchi, A. J . Chem.
Soc., Perkin Trans. 1 1996, 9, 875. (b) Alvaro, G.; Savoia, D. Tetrahe-
dron Asymmetry 1996, 7, 2083.
(20) Fishwich, M. F.; Wallbridge, M. G. H. J . Orgamet. Chem. 1977,
136, C46-C48.
(21) For the addition reaction of substituted chiral allyltrichlorotin
derivatives to R-iminoesters see: Hallett, D. J .; Thomas, E. J .
Tetrahedron Asymmetry 1995, 6, 2575.
(22) At this moment in time the formation of a heptacoordinated
complex (imine as a tridentate ligand) or, as widely reported for silicon,
the formation of a hexacoordinated cationic complex, resulting from
dissociation of a single chlorine ion cannot be excluded. For some
examples of silicon complexes dealing with the latter hypothesis, see:
(a) Denmark, S. E.; Stavenger, R. A. J . Am. Chem. Soc. 2000, 122,
8837. (b) Denmark, S. E.; Stavenger, R. A.; Wong, K. T.; Su, J . Am.
Chem. Soc. 1999, 121, 4982 and references therein. (c) Short, J . D.;
Attenoux, S.; Berrisford, D. J . Tetrahedron Lett. 1997, 38, 2351.
(14) For a similar transition state model proposed for asymmetric
Diels-Alder reactions performed on acrylic acid lactate esters, see: (a)
Hampley, P.; Helmchen, G.; Holmes, A. B.; Marshall, D. R.; MacKin-
non, J . W. M.; Smith, D. F.; Ziller, J . W. J . Chem. Soc. Chem. Commun.
1992, 786. (b) Poll, T.; Metter, J . O.; Helmchen, G. Angew. Chem., Int.
Ed. Engl. 1985, 24, 112.
(15) When the tert-butyl ester was replaced by the less sterically
demanding methyl ester, in the presence of TiCl4, a slightly reduced
stereocontrol was observed (17a /17b, 70:30 vs 80:20 for the methyl
ester and tert-butyl ester, respectively). This minimal dependence of
the diastereoselectivity on the kind of lactate ester used seems to
confirm this hypothesis.
(16) Reaction with the ate-complex allyl(ZnCH3)2MgCl in CH2Cl2 at
-78 °C furnished a complex mixture of reaction products.
(17) (a) Fishwick, M. F.; Wallbridge, M. G. H. J . Organomet. Chem.
1977, 136, C46-C48. (b) Alvaro, G.; Savoia, D. Tetrahedron Asymmetry
1996, 7, 2083.
J . Org. Chem, Vol. 67, No. 21, 2002 7323

Di Fabio et al.
SCHEME 4. Dia ster eoselective Syn th esis of Com p ou n d s 1 a n d 2a
a
(a) i. Allyltributyltin, CH2Cl2, SnCl4, -78 °C, 20 min, 90%; ii. 14, -78 °C, 20 min, 77%; (b) O3, CH2Cl2, -78 °C then PPh3, 2 h, 55%;
(c) tributyl-3-(1-phenylpiperidone) phosphonium bromide, DBU, CH3CN, -20 °C, 3 h, 70%; (d) Pd(PPh3)4, triethylamine, toluene, reflux,
3.5 h, 85%; (e) Pd(OAc)2, triethylamine, DMF, 120 °C, 3 h, 70%; (f) LiOH, THF/H2O 3:1, 1 h, rt, 85-90%.
same results were obtained when the reaction was
repeated on multigram scale, confirming both the degree
of diasteroselectivity achieved and the robustness of the
method. Having solved this key issue, the following
aldehyde derivative 22, prepared in good yield by ozo-
nolysis at -78 °C in CH2Cl2, was efficiently transformed
into the R,â-unsaturated γ-lactam intermediate 24 by
Wittig-type olefination reaction with tributyl-3-(1-phe-
nylpiperidone) phosphonium bromide6a 23 in CH3CN at
room temperature in the presence of a stoichiometric
amount of DBU. Good stereochemical control of the
double bond was observed (ratio E/Z ) 85:15) and the
desired E isomer was isolated in 70% yield by flash
chromatography. As expected, when 24 was submitted
to the following Heck-type ring closure reaction23 in DMF
in the presence of a catalytic amount of Pd(PPh3)4 and 2
equiv of TEA at 120 °C for 1 h, a mixture of the exo double
bond derivative 25 and the corresponding endo compound
26, readily separable by flash chromatography, was
obtained in 80% total yield (ratio 60:40).24 As far as
compound 26 is concerned, it is worth underlining that
the stereochemistry of the new C-4 stereogenic center was
completely controlled with the formation of the C-2/C-4
anti compound only. Finally, as expected, the hydrolysis
of the lactate ester gave the enantiomerically pure
compounds 1 and 2, without any detectable racemization.
As shown in Supporting Information, the 50% thermal
ellipsoid plot from the X-ray analysis of compound 1, as
its meglumine salt, confirmed the (R) absolute configu-
ration of the C-2 stereogenic center.25
To increase the efficiency of the synthetic route, this
Heck-type cyclization reaction was studied in more detail
with the aim of identifying reaction conditions to obtain
selectively either compound 25 or 26. The results ob-
tained are shown in Table 3. In this event, the Pd
catalyst, along with the solvent and reaction conditions,
were varied. First of all, no significant changes of the
ratio 25:26 was observed when the reaction was run for
(24) For a related example of an intramolecular cis addition/syn
elimination reaction, see: (a) Nagasawa, K.; Zako, Y.; Ishihara, H.;
Shimizu, I. J . Org. Chem. 1993, 58, 2523. (b) Nagasawa, K.; Zako, Y.;
Ishihara, H.; Shimizu, I. Tetrahedon Lett. 1991, 32, 4937.
(25) It should be noted that the numbering scheme of 1 in Support-
ing Information is arbitrary, and that C-9 in the diagram corresponds
to C-2.
(23) For reviews on the Heck reaction, see: (a) Gibson, S. E.;
Middleton, R. J .; Contemp. Org. Synth. 1996, 3, 447. (b) Cabri, W.;
Candiani, I. Acc. Chem. Res. 1995, 28, 2. (c) de Meijere, A.; Meyer, F.
E. Angew. Chem., Int. Ed. Engl. 1994, 36, 2379. (d) Heck, R. F. Org.
React. 1982, 27, 345.
7324 J . Org. Chem., Vol. 67, No. 21, 2002

Addition of Allylmetal Reagents to R-Imino Esters
TABLE 3. Heck Cycliza tion Rea ction : En d o/Exo Selectivity
entry
catalyst
Pd(PPh3)4, TEA (2 equiv)
Pd(PPh3)4, TEA (2 equiv)
Pd(OAc)2, PPh3, TEA (1 equiv)
Pd(OAc)2, TEA (1 equiv)
Pd(OAc)2, tri-o-tolylphosphine, TEA (1.5 equiv)
Pd(OAc)2, PPh3, Ag2CO3 (1.5 equiv)
Pd(PPh3)4, TEA (2 equiv)
solvent
T/t
25:26 (yield)
1
2
3
4
5
6
7
DMF
DMF
CH3CN
DMF
DMF
120 °C/1 h
120 °C/8 h
100 °C/6 h
110 °C/1 h
120 °C/3 h
120 °C/1 h
100 °C/3.5 h
60:40 (80%)
60:40 (80%)
55:45 (75%)
0:100 (70%)
0:100 (42%)
0:100 (63%)
96:4 (90%)
DMF
toluene
SCHEME 5. Heck Cycliza tion Rea ction : P r op osed Mech a n ism s
longer times, up to 8h (entry 2). Using Pd(OAc)2, PPh3,
and TEA in CH3CN at reflux a similar result in terms of
ratio the 25:26 was observed (entry 3), whereas, when
the reaction was performed with Pd(OAc)2 without the
addition of PPh3, compound 26 was isolated as the only
reaction product (entry 4). The same degree of regiose-
lectivity was observed with Pd(OAc)2 in the presence of
tri-2-o-tolylphosphine,26 or with PPh3 in the presence of
Ag2CO3 (entries 5 and 6, respectively).27 The complete
regiocontrol observed in the formation of the double bond,
could be explained based on the greater tendency of the
intermediate Pd-complex II (Scheme 5) to dissociate
dissociating solvent (toluene) is probably responsible for
the evolution of the system toward the preferential
formation, through the rotamer III, of the most thermo-
dynamically stable compound 25. Finally, as shown in
Scheme 6, when the Z-type olefin derivative 27 was
reacted with Pd(PPh3)4 and TEA, the derivative 26 was
obtained as the only reaction product, probably due to
the unfavored transformation, for steric reasons, of the
intermediate V into its rotational isomer VI. Based on
this result, to prepare compound 26 it was not necessary
to separate 24 from 27 and indeed, when the mixture of
the E and Z olefin derivatives (85:15) was reacted as
above, compound 26 was isolated in 85% yield after
purification by flash chromatography.
neutral ligands (such as DMF or tri-o-tolylphosphine26a
)
or iodide in the presence of Ag2CO3,27b to give compound
26 exclusively.
In conclusion, an efficient stereoselective synthesis of
novel THQ derivatives has been described. In particular,
the stereoselective formation of the C-2 R amino acid-
type stereogenic center was achieved using lactate as a
commercially available, low-cost chiral auxiliary, that can
be smoothly deprotected at the end of the synthetic
sequence. The stereoelectronic effect played by the ester
group of lactate, was hypothesized to be crucial to
suitably control the trajectory of approach of the nucleo-
phile to the N-aryl aldimine. At the same time, a high
degree of regioselectivity was achieved in the Heck-type
cyclization reaction. Following this route the exo and endo
compounds 1 and 2 were efficiently obtained on multi-
gram scale.
Remarkably, when the reaction was carried out with
Pd(PPh3)4 and TEA in toluene at 100 °C for 2 h, the
selectivity of the cyclization was completely reversed
(entry 7), and compound 25 and 26 were obtained in a
96:4 ratio in 90% total yield. In this case, the increased
stability of the intermediate Pd-complex II in a poor
(26) (a) Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C. P.;
Riermeier, T. H.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1844. (b) Mitsudo, T.; Fischetti, W.; Heck, R. F. J . Org. Chem.
1984, 49, 1640. (c) Ziegler, C. B.; Heck, R. F. J . Org. Chem. 1978, 43,
2941.
(27) (a) Larock, R. C.; Gong, W. H.; Baker, B. E. Tetrahedron Lett.
1989, 30, 2603. (b) Abelman, M. W.; Oh, T.; Overman, L. E. J . Org.
Chem. 1987, 52, 4133.
J . Org. Chem, Vol. 67, No. 21, 2002 7325

Di Fabio et al.
SCHEME 6. Heck Cycliza tion Rea ction : P r op osed Mech a n ism s
ter t-Bu tyl-(2R)-2-[(oxoa cetyl)oxy]p r op a n oa te (13). A
mixture of intermediate 12 (2.94 g, 15 mmol) in tetrahydro-
furan (60 mL) and water (20 mL) was reacted overnight at
room temperature with osmium tetroxide (4wt % in water, 2.6
mL, 0.4 mmol) and sodium periodate (8.0 g, 37 mmol). At the
end of the reaction the mixture was extracted with diethyl
ether (300 mL). The organic phase was separated, dried over
Na2SO4, concentrated in vacuo, and purified by flash chroma-
tography (cyclohexane/ethyl acetate 6:4) to give a colorless,
complex mixture of the different hydrate forms (3.3 g, 100%)
which was used as such in the next reaction.
Exp er im en ta l Section
All the reactions were performed in oven-dried glassware
under a positive pressure of nitrogen. Unless otherwise noted,
materials were obtained from commercial suppliers and used
without further purification. Tetrahydrofuran (THF) was
distilled from Na/benzophenone ketyl; dichloromethane was
distilled from P2O5; anhydrous DMF and CH3CN were from
commercial suppliers and used without further purification.
Analytical thin-layer chromatography (TLC) was performed
on precoated silica gel 60 F254 plates (0.25 mm); all Rf values
are determined visualizing all spots with UV light (254 nm)
and/or phosphomolybdic acid solution. Flash chromatography
was performed on silica gel 60 (230-400 mesh). 1H and 13C
NMR spectra (400 MHz and 500 MHz) were recorded at 25 °C
and J values are given in hertz. In the 1H NMR spectra,
chemical shifts are reported in ppm to the residual solvent
line downfield from the TMS line (as external reference) while
in the carbon NMR spectra, the center line 13C resonance of
DMSO-d6 was used as internal reference. NMR assignments
are assisted by NOE and 2D-techniques. IR spectra were
recorded in CDCl3 solution unless otherwise indicated and are
reported in wavenumbers (cm-1). Mass spectra were recorded
in FAB mode, unless otherwise stated. Melting points (mp)
are uncorrected. All optical rotation [R]D values were obtained
in solution, at the sodium D line, at 20 °C. Crystal structure
analysis data were collected using ω rotation with narrow
frames.
ter t-Bu tyl-(2R)-2-({(2E)-2-[(5-ch lor o-2-iodoph en yl)im in o]-
eth a n oyl}oxy) p r op a n oa te (14). A solution of compound 13
(3.3 g, 15 mmol) in toluene (200 mL) was refluxed for 1 h in
the presence of a Dean-Stark apparatus. After cooling to room
temperature, 5-chloro-2-iodoaniline (4.3 g, 17 mmol) was
added, and the solution was refluxed in the presence of MgSO4
for 2 h. After filtration of the MgSO4, the solvent was
concentrated in vacuo affording the title compound (6.6 g, 15
mmol, 100%) as a colorless oil, which was used without
purification in the next reaction.
(1R) a n d (1S)-2-(ter t-Bu toxy)-1-m eth yl-2-oxoeth yl-2-(5-
ch lor o-2-iod oa n ilin o)-4-p en ten oa te (15a ,b). A solution of
intermediate 14 (1 g, 2.22 mmol) in dry dichloromethane (30
mL) was cooled to -78 °C, and TiCl4 (1 M in toluene, 2.44 mL,
2.44 mmol) was added dropwise. After 15 min, allyltributyltin
(1.1 g, 3.33 mmol) was added, and the resulting suspension
was stirred for 1 h. At the end of the reaction, a saturated
solution of NH4Cl (100 mL) was added, and the resulting
mixture was extracted with ethyl acetate (2 × 200 mL). The
organic layer were collected then washed with brine and dried
over Na2SO4. After filtration, the solvent was concentrated in
vacuo and the crude residue purified by flash chromatography
(cyclohexane/ethyl acetate 95/5) to afford a 80:20 mixture of
diasteroisomers 15a and 15b by HPLC analysis, as a colorless
oil (0.9 g, 90%).
(1R)-2-ter t-Bu toxy-1-m eth yl-2-oxoeth yl Acr yla te (12).
A solution of acryloyl chloride (3.1 mL, 37.4 mmol) in dichlo-
romethane (50 mL) was added dropwise, at 0 °C under a
nitrogen atmosphere, to a mixture of (R)-tert-butyl lactate 11
(2.5 g, 17 mmol), triethylamine (5.4 mL, 37.4 mmol) and
4-(dimethylamino)pyridine (0.415 g, 3.4 mmol) in dry dichlo-
romethane (100 mL). The resulting solution was stirred for
1h at 0 °C and then at room temperature for 2 h. At the end
of the reaction 1 M hydrochloric acid (300 mL) was added
followed by ethyl acetate (400 mL). The organic layer was
separated and washed with brine (300 mL) and then dried over
Na2SO4 and concentrated in vacuo. The crude residue was
purified by flash chromatography (cyclohexane/ethyl acetate
85:15) to give the title compound 12 (3.0 g, 88%) as a colorless
oil. IR (film): 1746, 1731 cm-1; 1H NMR (DMSO) δ 6.36 (dd, J
) 16.8 Hz, 1.5 Hz, 1H), 6.22 (dd, J ) 10.5 Hz, 16.8 Hz, 1H),
5.99 (dd, J ) 10.5 Hz, 1.5 Hz, 1H), 4.89 (q, J ) 6.80 Hz, 1H),
1.40 (d, J ) 6.80 Hz, 3H), 1.39 (s, 9H). MS: m/z ) 200 [M +
(1R)-2-(ter t-Bu tyl)- 1-m eth yl-2-oxoeth yl-(2S)-2-(5-ch lor o-
2-iod oa n ilin o)-4-p en ten oa te (15a ). To allyltributyltin (2.7
g, 8.18 mmol) dissolved in dichloromethane (100 mL) was
added, dropwise at -78 °C, SnCl4 (1 M solution in toluene,
8.2 mL, 8.2 mmol). The solution was stirred for 20 min, and
then intermediate 14 (2.39 g, 5.46 mmol) dissolved in dry
dichloromethane (50 mL) was added. The reaction was stirred
at -78 °C for 15 min, and then a saturated solution of NH4Cl
(100 mL) was added and the resulting mixture was extracted
with ethyl acetate (2 × 200 mL). The organic layers were
collected and washed with a 10% solution of KF in water. The
H]+. [R]20 41.2 (c 1.1, CHCl3). Anal. Calcd for C10H16O4: C,
D
59.98; H, 8.05. Found C, 59.80; H, 8.00.
7326 J . Org. Chem., Vol. 67, No. 21, 2002

Addition of Allylmetal Reagents to R-Imino Esters
organic phase was diluted with diethyl ether (200 mL), filtered,
dried over Na2SO4, and evaporated in vacuo. Final purification
of the crude residue by flash chromatography (cyclohexane/
ethyl acetate 95:5) gave the title compound 15a as colorless
solution was taken up with ethyl acetate (100 mL) and washed
with NH4Cl (100 mL) and then with brine, dried over Na2-
SO4, and evaporated in vacuo. The final purification of the
crude residue by flash chromatography (cyclohexane/dichlo-
romethane/ethyl acetate 7:2.5:0.5) afforded compound 26 (0.24
oil (2.02 g, 77%). [R]20 78 (c 0.077, CHCl3) IR (CDCl3): 3376,
D
1740 cm-1; H NMR (CDCl3) δ 7.55 (d, J ) 8.5 Hz, 1H), 6.47
1
g, 70%) as a white foam. [R]20 -48.8 (c 0.19, CHCl3). IR
D
(Nujol): 3380, 1741, 1681 cm-1
;
1H NMR (DMSO-d6) δ 7.80
(dd, J ) 8.5 Hz, 2.5 Hz, 1H), 6.43 (d, J ) 2.5 Hz, 1H), 5.88 (m,
1H), 5.27 (m, 2H), 5.05 (q, J ) 6.82 Hz, 1H), 4.78 (bd, J ) 6.5
Hz, 1H), 4.18 (m, 1H), 2.74 (m, 2H), 1.52 (d, J ) 6.82 Hz, 3H),
1.47 (s, 9H). Anal. Calcd for C18H23ClINO4: C, 45.07; H, 4.83;
N, 2.92. Found C, 45.15; H, 4.85; N, 2.95.
(m, 2H), 7.39 (m, 2H), 7.12 (m, 1H), 6.82 (d, J ) 8.5 Hz, 1H),
6.77 (d, J ) 2.5 Hz, 1H), 6.70 (m, 1H), 6.49 (dd, J ) 8.5 Hz,
2.5 Hz, 1H), 6.46 (bm, NH), 4.93 (q, J ) 7.2 Hz, 1H), 4.49 (m,
2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.44 (m, 1H), 2.00 (m, 1H),
1.39 (s, 9H), 1.38 (d, J ) 7.2 Hz, 3H). Anal. Calcd for C27H29
-
(1R)-2-ter t-Bu tyl-1-m eth yl-2-oxoeth yl-(2S)-2-(5-ch lor o-
2-iod oa n ilin o)-4-oxobu ta n oa te (22). Intermediate 15a (2 g,
4.2 mmol) was dissolved in dichloromethane (200 mL); at -78
°C ozone was bubbled through the solution until the color
turned red. Triphenylphosphine (4.4 g, 16.8 mmol) was then
added, and the reaction mixture was stirred for 2 h. After
evaporation of the solvent in vacuo, the crude mixture was
purified by column chromatography (cyclohexane/ethyl acetate
ClN2O5: C, 67.23; H, 5.64; N, 6.82. Found: C, 67.35; H, 5.75;
N, 6.70.
Sod iu m (2R,4E)-7-Ch lor o-4-(2-oxo-1-p h en yl-3-p yr r o-
lid in ylid e n e )-1,2,3,4-t e t r a h yd r o-2-q u in olin e ca r b oxy-
la te (1). To a solution of intermediate 25 (0.29 g, 0.72 mmol)
in THF/H2O (3:1) (14 mL) was added LiOH (0.069 g, 2.88
mmol), and the reaction was stirred at room temperature for
1 h. At the end of the reaction the THF was evaporated in
vacuo. H2O (50 mL) was added and 3 N HCl was added
dropwise until an extensive precipitation occurred (pH 3). The
solid was filtered, washed with water (2 × 10 mL), and dried
in vacuo at 60 °C for 12 h. The solid was dissolved in a 5%
solution of methanol in ethanol (20 mL), and a 1 N NaOH
solution (0.8 mL, 0.8 mmol) was added. At the end of the
reaction, diethyl ether (10 mL) to the resulting suspension was
added, and the solid was filtered, washed with diethyl ether
(10 mL), and dried in vacuo at 40 °C for 12 h, to give compound
1 (0.24 g, 90%) as a yellow solid. Mp >200 °C; [R]D -603.7° (c
0.316, DMSO); IR (Nujol): 1670, 1596 cm-1; 1H NMR (DMSO-
d6) δ 7.79 (m, 2H), 7.42 (m, 2H), 7.17 (d, J ) 8.5 Hz, 1H), 7.16
(m, 1H), 6.82 (d, J ) 2.5 Hz, 1H), 6.43 (dd, J ) 8.5 Hz, 2.5 Hz,
1H), 6.17 (bm, 1H), 4.53 (m, 1H), 3.83 (m, 2H), 3.40 (m, 1H),
3.28 (m, 1H), 2.93 (m, 1H), 2.06 (m, 1H); 13C NMR (DMSO-d6)
ppm 173.34, 168.74, 148.61, 141.82, 140.91, 134.73, 129.99,
134.73, 129.99, 129.34, 124.44, 123.37, 119.81, 117.94, 113.82,
113.65, 55.61, 45.69, 27.98, 27.09. Anal. Calcd for C20H16ClN2-
NaO3: C, 61.47; H, 4.13; N, 7.17; Na, 5.88. Found: C, 61.35;
H, 3.95; N, 6.99; Na, 5.95.
Cr ysta l Str u ctu r e An a lysis of th e Meglu m in e Sa lt of
Com p ou n d 1. A suitable crystal was grown by slow evapora-
tion of a DMF solution. Crystal data: C20H17ClN2O3‚C7H17NO5,
M ) 564.02, monoclinic, P21 yellow crystals, a ) 5.7595(3) Å,
b ) 14.2904(8) Å, c ) 16.2413(9) Å, R ) 90°, â ) 94.823(2)°, γ
) 90°, 160 K, Z ) 2, Final R indices [F2 > 2σ] ) 0.0343, GOF
) 1.074. Data were collected on a Bruker SMART 1K CCD
diffractometer using ω´ rotation with narrow frames. The
structure was solved using direct methods. Full-matrix least-
squares refinement was employed with anisotropic thermal
parameters for all non-hydrogen atoms. Hydrogen atoms were
refined isotropically in riding mode. Full details can be found
in the Supporting Information.
85/15) to afford the title compound 22 (1.1 g, 55%). [R]20 26.1
D
1
(c 0.65, CHCl3) IR (CDCl3): 1739 (CdO); H NMR (CDCl3) δ
9.85 (m, 1H), 7.57 (d, J ) 9.5 Hz, 1H), 6.58 (d, J ) 2.5 Hz,
1H), 6.51 (dd, J ) 9.5 Hz, 2.5 Hz, 1H), 5.04 (q, J ) 6.82 Hz,
1H), 4.96 (bd, J ) 8.4 Hz, 1H), 4.62 (m, 1H), 3.20 (m, 1H),
3.06 (m, 1H), 1.50 (m, 12H). Anal. Calcd for C17H21ClINO5: C,
42.39; H, 4.39; N, 2.91. Found C, 42.28; H, 4.30; N, 2.85.
(1R)-2-ter t-Bu t oxy-1-m et h yl-2-oxoet h yl-(2S,4E)-2-(5-
ch lor o-2-iod oa n ilin o)-4-(2-oxo-1-p h e n yl-3-p yr r olid i-
n ylid en e)bu ta n oa te (24). To a solution of intermediate 22
(1.1 g, 2.3 mmol) in acetonitrile (60 mL) were added tributyl-
3-(1-phenylpiperidone) phosphonium bromide 23 (1.5 g, 3.45
mmol) and DBU (0.5 mL, 3.4 mmol). The mixture was reacted
at -20 °C for 3 h. 1 N HCl (50 mL) and ethyl acetate (200
mL) were added. The organic layer was separated, washed
with brine, dried over Na2SO4, and concentrated in vacuo to
afford a mixture 85:15 of isomer (E/Z). Final purification by
flash chromatography (cyclohexane/ethyl acetate 85:15) af-
forded the title compound 24 (1.05 g, 70%) as a white solid.
Mp 36-39 °C; [R]20D +22° (c ) 0.16, DMSO). IR (Nujol): 1741,
1694, 1660 cm-1; 1H NMR (CDCl3) δ 7.75 (m, 2H), 7.63 (d, J )
8.9 Hz, 1H), 7.37 (m, 2H), 7.14 (m, 1H), 6.74 (d, J ) 2.7 Hz,
1H), 6.52 (dd, J ) 8.9 Hz, 2.7 Hz, 1H), 6.41 (m, 1H), 4.97 (m,
2H), 4.72 (m, 1H), 3.84 (m, 2H), 2.80 (m, 2H), 2.66 (m, 2H),
1.40 (m, 12H). Anal. Calcd for C27H30ClIN2O5: C, 51.90; H,
4.84; N, 4.48. Found: C, 51.95; H, 4.90; N, 4.42.
(1R)-2-ter t-Bu toxy-1-m eth yl-2-oxoeth yl-(2R,4E)-7-ch lor o-
4-(2-oxo-1-ph en yl-3-pyr r olidin yliden e)-1,2,3,4-tetr ah ydr o-
2-qu in olin eca r boxyla te (25). To a solution of intermediate
24 (0.5 g, 0.84 mmol) in toluene (100 mL) were added
Pd(PPh3)4 (0.29 g, 0.25 mmol) and triethylamine (0.16 mL, 1.17
mmol), and the mixture was heated to 110 °C for 3.5 h under
an argon atmosphere. At the end of the reaction ethyl acetate
(300 mL) was added. The organic phase was washed with NH4-
Cl (100 mL) and then brine, dried over Na2SO4, and evaporated
in vacuo. Purification of the crude residue by flash chroma-
tography (cyclohexane/dichloromethane/ethyl acetate 6.5/3/0.5)
gave the title compound 25 (0.296 g, 85%) as a yellow foam.
Sod iu m (2R,4S)-7-Ch lor o-4-(2-oxo-1-p h en yl-2,5-d ih y-
d r o-1H -p yr r ol-3-yl)-1,2,3,4-t et r a h yd r o-2-q u in olin eca r -
boxyla te (2). To a solution of intermediate 26 (0.24 g, 0.59
mmol) in THF/H2O (3:1) (10 mL) was added LiOH (0.060 g,
2.50 mmol), and the reaction was stirred for 1 h at room
temperature. The organic solvent was evaporated in vacuo,
and H2O (50 mL) was added. HCl (3 N) was added until
extensive precipitation occurred (pH 3). The solid was filtered,
washed with water (2 × 10 mL), and dried in vacuo at 60 °C
for 12 h. The solid was then dissolved in a 5% solution of
methanol in ethanol (15 mL), and a 1 N solution of NaOH (0.7
mL) was added. Diethyl ether (10 mL) was added to the
resulting suspension. The solid was filtered, washed with
diethyl ether (10 mL), and dried in vacuo at 40 °C for 12 h to
give the title sodium salt (0.186 g, 85%) as a white solid. Mp
[R]20 -194.4 (c 0.692, CHCl3). IR (Nujol): 3370, 1743, 1684
D
1
cm-1; H NMR (DMSO-d6) δ 7.73 (m, 2H), 7.36 (m, 2H), 7.21
(d, J ) 8.5 Hz, 1H), 7.11 (m, 1H), 6. 98 (bm, NH), 6.75 (d, J )
2.5 Hz, 1H), 6.57 (dd, J ) 8.5 Hz, 2.5 Hz, 1H), 4.70 (q, J ) 7.4
Hz, 1H), 4.24 (m, 2H), 3.75 (m, 1H), 3.18 (m, 1H), 2.05 (m,
1H), 2.94 (m, 1H), 1.25 (s, 9H), 1.23 (d, J ) 7.4 Hz, 3H). Anal.
Calcd for C27H29ClN2O5: C, 67.23; H, 5.64; N, 6.82. Found: C,
67.00; H, 5.45; N, 6.72.
(1R)-2-ter t-Bu toxy-1-m eth yl-2-oxoeth yl (2R,4S)-7-ch lor o-
4-(2-oxo-1-p h en yl-2,5-d ih yd r o-1H-p yr r ol-3-yl)-1,2,3,4-tet-
r a h yd r o-2-qu in olin eca r boxyla te (26). To a solution of
intermediate 24 (0.5 g, 0.84 mmol) in DMF (20 mL) were added
Pd(OAc)2 (0.05 g, 0.25 mmol) and triethylamine (0.16 mL, 1.17
mmol), and the reaction mixture was stirred at 120 °C for 3 h
under argon atmosphere. At the end of the reaction the
> 200 °C; [R]20 -102.3° (c 0.09, DMSO) IR (Nujol): 3383,
D
1669, 1598 cm-1; 1H NMR (DMSO-d6) δ 7.79 (m, 2H), 7.37 (m,
2H), 7.10 (m, 1H), 6.80 (d, J ) 8.5 Hz, 1H), 6.72 (d, J ) 2.5
Hz, 1H), 6.36 (m, 1H), 6.34 (dd, J ) 8.5 Hz, 2.5 Hz, 1H), 5.71
J . Org. Chem, Vol. 67, No. 21, 2002 7327

Di Fabio et al.
(bm, 1H), 4.53-4.35 (m, 2H), 3.76 (m, 1H), 3.13 (m, 1H), 2.26
(m, 1H), 1.43 (m, 1H). Anal. Calcd for C20H16ClN2NaO3: C,
61.47; H, 4.13; N, 7.17; Na, 5.88. Found: C, 61.39; H, 4.01; N,
7.01; Na, 5.92.
ethyl acetate (2 × 100 mL). The organic layers were collected
and washed with a 10% solution of KF in water. The organic
phase was diluted with diethyl ether (50 mL), filtered, dried
over Na2SO4, and evaporated in vacuo. Final purification of
the crude residue by flash chromatography (cyclohexane/ethyl
acetate 95:5) gave the title compound 17a as colorless oil.
ter t-Bu t yl-(2R)-2-({(2E)-2-[(4-m et h oxyp h en yl)im in o]-
eth a n oyl}oxy)p r op a n oa te (16). A solution of 4-methoxya-
niline (0.47 g, 3.8 mmol) dissolved in toluene (5 mL) was added
to the glyoxylate ester 13 (1 g, 4.5 mmol), and the solution
was refluxed for 30 min in the presence of a Dean-Stark
apparatus. The solvent was evaporated in vacuo obtaining
aldimine 16, as a brown oil, in quantitative yield, which was
used as such in the next reaction without purification. IR (film)
(1R)-2-ter t-Bu toxy-1-m eth yl-2-oxoeth yl-(2S)-2-(4-m eth -
oxya n ilin o) p en ta n oa te (18). To a solution of 17a (0.25 g,
0.72 mmol) in ethanol (10 mL) was added Pd/C 10% (0.18 g),
and the mixture was hydrogenated in a Parr apparatus at 4
atm for 6 h. At the end of the reaction the catalyst was filtered
and the solvent was evaporated in vacuo: 0.23 g (92%) of 18,
as white wax, was obtained after flash chromatography
1
1744, 1721, 1623, 1589 cm-1. H NMR (CDCl3) δ 8.01 (s, 1H),
(cyclohexane/ethyl acetate 8:2). [R]20 88.1 (c 1.24, CHCl3) IR
7.39 (d, 2H), 6.95 (d, 2H), 5.20 (q, J ) 6.80 Hz, 1H), 3.85 (s,
3H), 1.60 (d, J ) 6.80 Hz, 3H), 1.50 (s, 9H). 13C NMR (CDCl3)
ppm 169.13, 162.70, 160.62 141.34,147.10, 124.05, 114.02,
81.80, 70.01, 55.03, 27.03, 16.30. MS (FAB) m/z ) 308 [MH]+,
252 [MH - t-Bu + H]+, 180. Anal. Calcd for C16H21NO5: C,
62.53; H, 6.89; N, 4.56; O, 26.03. Found C, 62.78; H, 6.96; N
4.43; O 26.09.
D
(CHCl3) 1739, 1511 cm-1. 1H NMR (CDCl3) δ 6.76 (m, 2H), 6.61
(m, 2H), 4.96 (q, J ) 6.50 Hz, 1H), 4.04 (m, 1H), 3.74 (s, 3H),
1.92 (m, 1H), 1.78 (m, 1H), 1.57 (m, 2H), 1.46 (d, J ) 6.50 Hz,
3H), 1.45 (s, 9H), 0.99 (t, 3H). MS (ES) m/z ) 352 [MH]+, 296
[MH - tBu + H]+, 178, 123. Anal. Calcd for C19H29NO5: C,
64.93; H, 8.32; N, 3.99; O, 22.76. Found C, 65.01; H, 8.21; N
4.03; O 22.80.
General Procedure for the Allylmetalation Reaction (Lewis
acids): (1R)-2-tert-Butoxy-1-methyl-2-oxoethyl-2-(4-methoxya-
nilino)-4-pentenoate (17a,b). To the aldimine 16 (0.37 g, 1.2
mmol) dissolved in dry CH2Cl2 (4 mL) was slowly added the
Lewis acid (1.3 mmol) at -78 °C under a nitrogen atmosphere.
After 20 min, allyltributyltin (0.45 mL, 1.4 mmol) was added.
The reaction mixture was stirred for an additional 30 min,
and then a saturated solution of NH4Cl (5 mL) and ethyl
acetate (16 mL) was added. The organic phase was separated
and washed with brine and dried over Na2SO4, and the solvent
was evaporated in vacuo. The crude residue was purified by
flash chromatography (cyclohexane/ethyl acetate 8:2) to give
a mixture of the two diastereoisomers.
Gen er a l P r oced u r e for th e Allylm eta la tion Rea ction
(Br o1n sted a cid s). (1R)-2-ter t-Bu toxy-1-m eth yl-2-oxoet-
h yl-2-(4-m eth oxya n ilin o)-4-p en ten oa te (17a ,b). To the al-
dimine 16 (0.37 g, 1.2 mmol) dissolved in dry CH2Cl2 (4 mL)
was slowly added the Bro¨nsted acid (1.3 mmol) at -78 °C
under a nitrogen atmosphere. After 20 min, allyltributyltin
(0.45 mL, 1.4 mmol) was added. The reaction mixture was
stirred for an additional 30 min, and then a saturated solution
of NH4Cl (5 mL) and ethyl acetate (16 mL) was added. The
organic phase was separated and washed with brine and dried
over Na2SO4, and the solvent was evaporated in vacuo. The
crude residue was purified by silica flash chromatography
(cyclohexane/ethyl acetate 8:2) to give a mixture of the two
diastereoisomers.
(2S)-2-(4-Meth oxya n ilin o)p en ta n oic a cid (19). A solu-
tion of 18 (0.23 g, 0.65 mmol) in a 2:1 mixture of THF/H2O
(15 mL) and LiOH‚H2O (0.11 g, 2.62 mmol) was stirred at room
temperature for 4 h. After evaporation of the THF in vacuo,
H2O (5 mL) and diethyl ether (30 mL) was added. After
separation, the aqueous phase was acidified with HCl 5% to
pH 3; the white solid precipitate was filtered and dried in
vacuo to give the title compound 19 (0.1 g, 66%). [R]20 71.0 (c
D
1
1.18, DMSO). mp ) 180 °C. H NMR (DMSO) δ 6.70 (m, 2H),
6.52 (m, 2H), 3.75 (m, 1H), 3.62 (s, 3H), 1.66 (m, 2H), 1.40 (m,
2H), 0.89 (t, 3H). MS (ES) m/z ) 222 [MH]+, 175 [M -
COOH]+. Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27;
O, 21.5. Found C, 65.23; H, 7.55; N 6.32; O 21.4.
Meth yl-(2S)-2-(4-m eth oxya n ilin o)p en ta n oa te (20). A
solution of trimethylsilyl diazomethane (2 M in hexane, 0.4
mL, 0.80 mmol) was added, at room temperature under a
nitrogen atmosphere, to compound 19 (0.08 g, 0.31 mmol)
dissolved in a 1:1 mixture of CH2Cl2/CH3OH (6 mL). After 2 h
the solvent was evaporated in vacuo, and the crude residue
was purified by flash chromatography (cyclohexane/ethyl
acetate 8:2) to give the title compound 20 (0.067 g, 90%) as a
yellow oil. [R]20 60.1 (c 1.03, CHCl3) IR (Nujol) 3363, 1723
D
cm-1. H NMR (CDCl3) δ 6.77 (m, 2H), 6.60 (m, 2H), 4.00 (m,
1
1H), 3.83 (broad m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 1.83-1.70
(m, 2H), 1.46 (m, 2H), 0.97 (t, 3H). MS (ES) m/z ) 238 [MH]+,
178. Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90; O,
20.23. Found C, 65.73; H 7.17; N 5.82; O 20.30.
17a : [R]20D 91.8 (c 0.69, CHCl3). IR (CHCl3) 1739, 1510 cm-1
.
1H NMR (CDCl3) δ 6.77 (m, 2H), 6.60 (m, 2H), 5.88 (m, 1H),
5.22-5.18 (m, 2H), 4.99 (q, J ) 6.82 Hz, 1H), 4.12 (m, 1H),
3.88 (m, 1H), 3.74 (s, 3H), 2.71 (m, 1H), 2.63 (m, 1H), 1.47 (d,
J ) 6.82 Hz, 3H), 1.46 (s, 9H). MS (FAB) m/z ) 349, 294 [MH
- t-Bu + H]+, 252, 176.: Anal. Calcd for C19H27NO5: C, 65.32;
H, 7.79; N, 4.01; O, 22.89. Found C, 65.51; H, 7.82; N 4.03; O
22.98.
Meth yl (2S)-2-Am in op en ta n oa te (21). To a solution of
intermediate 20 (0.064 g, 0.27 mmol) dissolved in acetonitrile
(7.5 mL) was added, at -25 °C under a nitrogen atmosphere,
ammonium cerium nitrate (0.48 g, 0.88 mmol) dissolved in H2O
(0.8 mL). The reaction mixture was stirred for 40 min, and
then the solvent was removed in vacuo. The aqueous solution
diluted with H2O (1.5 mL) was washed with diethyl ether (2
× 5 mL), and then NaOH 0.5 M was added dropwise to pH 8
and extracted with CH2Cl2 (3 × 5 mL). The organic layers were
collected, and the solvent was evaporated in vacuo. Finally,
the crude residue was purified by flash chromatography (100%
ethyl acetate) to give title compound 21 (0.016 g, 45%) as a
17b: [R]20 -14.8 (c 0.0.65, CHCl3). IR (CHCl3) 1739, 151
D
cm-1. H NMR (CDCl3) δ 6.78 (m, 2H), 6.61 (m, 2H), 5.86 (m,
1
1H), 5.22-5.18 (m, 2H), 4.99 (q, J ) 6.52 Hz, 1H), 4.13 (bm,
1H), 3.88 (bm, 1H), 3.74 (s, 3H), 2.64 (m, 2H), 1.44 (s, 9H),
1.41 (d, J ) 6.52 Hz, 3H).). MS (FAB) m/z ) 349, 294 [MH -
t-Bu + H]+, 252, 176. Anal. Calcd for C19H27NO5: C, 65.32; H,
7.79; N, 4.01; O, 22.89. Found C, 65.66; H, 7.90; N 4.10; O
22.90.
(1R)-2-ter t-Bu toxy-1-m eth yl-2-oxoeth yl-2-(4-m eth oxya -
n ilin o)-4-p en ten oa te (17a ). To allyltributyltin (1.6 g, 4.86
mmol) dissolved in dichloromethane (50 mL) was added
dropwise at -78 °C SnCl4 (1 M solution in toluene, 4.9 mL,
4.9 mmol). The solution was stirred for 20 min, and then
intermediate 16 (1 g, 3.24 mmol), dissolved in dry dichlo-
romethane (25 mL) was added. The reaction was stirred at
-78 °C for 15 min, then a saturated solution of NH4Cl (50
mL) was added, and the resulting mixture was extracted with
pale yellow oil. [R]20 -15.3 (c 0.57, DMSO). IR (CHCl3) 2961,
D
1733 cm-1. H NMR (CDCl3) δ 3.74 (s, 3H), 3.47 (m, 1H), 1.71
1
(m, 2H), 1.55 (m, 2H), 1.42 (m, 2H), 0.95 (t, 3H). MS (ES) m/z
) 132 [MH]+. Anal. Calcd for C6H13NO2: C, 54.94; H, 9.99; N,
10.68; O, 24.39. Found C, 55.01; H 9.86; N 10.70; O 24.48.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 1, 2, 17a , 17b, 15a , 22, 24, 25. X-ray crystal-
lographic data for compound 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O020327D
7328 J . Org. Chem., Vol. 67, No. 21, 2002