Stereoselective formal [3 + 2] cycloaddition of N-alkylidene glycine ester anions to chiral fischer alkenylcarbene complexes. Asymmetric synthesis of 3,4,5-trisubstituted prolines

Article abstract of DOI:10.1021/jo010485p

The reaction between N-alkylidene glycine ester enolates, generated from glycine esters aldimines with LDA in THF at low temperature, and chiral alkoxyalkenylcarbene complexes of chromium provided directly 2,4,5-trisubstituted-3-pyrrolidinylcarbene complexes with total exo selectivity and very high syn and facial diastereoselectivity when carbene complexes bearing the (-)-8-phenylmenthyloxy group were employed. Oxidation of the metal carbene moiety followed by basic hydrolysis of the esters afforded enantiomerically highly enriched syn, exo-3,4,5-trisubstituted prolines, whereas acidic hydrolysis of the same functional groups proceeded with epimerization at the α-amino acid center leading to anti,exo-3,4,5-trisubstituted prolines of very high enantiomeric purity as well.

Full text of DOI:10.1021/jo010485p

648
J . Org. Chem. 2002, 67, 648-655
Ster eoselective F or m a l [3 + 2] Cycloa d d ition of N-Alk ylid en e
Glycin e Ester An ion s to Ch ir a l F isch er Alk en ylca r ben e
Com p lexes. Asym m etr ic Syn th esis of 3,4,5-Tr isu bstitu ted P r olin es
Isabel Merino, Santosh Laxmi Y. R.,§ J osefa Flo´rez, and J ose´ Barluenga*
Instituto Universitario de Quı´mica Organometa´lica “Enrique Moles”-Unidad Asociada al CSIC,
Universidad de Oviedo, J ulia´n Claverı´a 8, 33071 Oviedo, Spain
J esu´s Ezquerra and Concepcio´n Pedregal*
Centro de Investigacio´n Lilly, S. A. Avda. de la Industria 30, Alcobendas, 28108 Madrid, Spain
barluenga@sauron.quimica.uniovi.es
Received May 11, 2001
The reaction between N-alkylidene glycine ester enolates, generated from glycine esters aldimines
with LDA in THF at low temperature, and chiral alkoxyalkenylcarbene complexes of chromium
provided directly 2,4,5-trisubstituted-3-pyrrolidinylcarbene complexes with total exo selectivity and
very high syn and facial diastereoselectivity when carbene complexes bearing the (-)-8-phenyl-
menthyloxy group were employed. Oxidation of the metal carbene moiety followed by basic hydrolysis
of the esters afforded enantiomerically highly enriched syn,exo-3,4,5-trisubstituted prolines, whereas
acidic hydrolysis of the same functional groups proceeded with epimerization at the R-amino acid
center leading to anti,exo-3,4,5-trisubstituted prolines of very high enantiomeric purity as well.
In tr od u ction
Since then, other chiral cyclic and acyclic azomethine
ylides have been developed to achieve asymmetric control
in the reaction.2,5c,7 Another strategy to obtain optically
active cycloadducts is the use of a chiral dipolarophile.2,5c,8
R,â-Unsaturated ketones, esters, and amides bearing a
chiral auxiliary bonded to the â-position8c,d,h,k or in the
amino8g or alkoxy groups8b,e,j of the R,â-unsaturated
carbonyl system have been used for this purpose. In this
context, Grigg et al. have used chiral menthyl acrylates
in the reaction with azomethine ylides derived from
amino esters to obtain enantiomerically enriched pro-
line esters with high diastereoselectivity.5c,8b,j,k Also,
asymmetric induction in the cycloaddition of azomethine
ylides derived from R-amino esters with R,â-unsaturated
esters can be achieved in the presence of a chiral
[3 + 2] Cycloaddition reactions between 1,3-dipoles and
alkenes is the most efficient method to obtain five-
membered heterocyclic rings.1 The possibility of control-
ling the stereochemical outcome of this reaction has
converted it into a very powerful tool in synthetic
chemistry.2 The dipolar cycloaddition of azomethine
ylides derived from R-amino esters to substituted alkenes
furnishes proline derivatives, usually in a regio- and
stereocontrolled fashion.2,3 N-Metalated azomethine ylides
are commonly generated from the corresponding amino
ester by treatment with a base (Et3N or DBU) in the
presence of either a lithium or a silver salt. The groups
of Kanemasa4 and Grigg5 have published extensive work
in this field.
catalyst.2,5c,9
.
Padwa et al.6 were the first who employed a chiral
azomethine ylide to obtain optically active pyrrolidines.
(7) Chiral 1,3-dipoles: (a) Anslow, A. S.; Harwood, L. M.; Phillips,
H.; Watkin, D. Tetrahedron: Asymmetry 1991, 2, 169. (b) Deprez, P.;
Royer, J .; Husson, H.-P. Tetrahedron: Asymmetry 1991, 2, 1189. (c)
Williams, R. M.; Zhai, W.; Aldous, D. J .; Aldous, S. C. J . Org. Chem.
1992, 57, 6527. (d) Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Soma-
sunderam, A. Tetrahedron 1993, 49, 8679. (e) Garner, P.; Dogan, O.
J . Org. Chem. 1994, 59, 4. (f) Anslow, A. S.; Harwood, L. M.; Lilley I.
A. Tetrahedron: Asymmetry 1995, 6, 2465.
(8) Chiral dipolarophiles: (a) Garner, P.; Ho, W. B. J . Org. Chem.
1990, 55, 3973. (b) Barr, D. A.; Dorrity, M. J .; Grigg, R.; Malone, J . F.;
Montgomery, J .; Rajviroongit, S.; Stevenson, P. Tetrahedron Lett. 1990,
31, 6569. (c) Kanemasa, S.; Hayashi, T.; Tanaka, J .; Yamamoto, H.;
Sakurai, T. J . Org. Chem. 1991, 56, 4473. (d) Annunziata, R.; Cinquini,
M.; Cozzi, F.; Raimondi, L.; Pilati, T. Tetrahedron: Asymmetry 1991,
2, 1329. (e) Coulter, T.; Grigg, R.; Malone, J . F.; Sridharan, V.
Tetrahedron Lett. 1991, 32, 5417. (f) Garner, P.; Ho, W. B.; Shin, H. J .
Am. Chem. Soc. 1992, 114, 2767. (g) Waldmann, H.; Bla¨ser, E.; J ansen,
M.; Letschert, H.-P. Chem. Eur. J . 1995, 1, 150. (h) Galley, G.;
Liebscher, J .; Pa¨tzel, M. J . Org. Chem. 1995, 60, 5005. (i) Pyne, S. G.;
Safei-G., J .; Koller, F. Tetrahedron Lett. 1995, 36, 2511. (j) Barr, D.
A.; Dorrity, M. J .; Grigg, R.; Hargreaves, S.; Malone, J . F.; Montgomery,
J .; Redpath, J .; Stevenson, P.; Thornton-Pett, M. Tetrahedron 1995,
51, 273. (k) Cooper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P.;
Redpath, J . Tetrahedron 1995, 51, 7791. (l) Fray, A. H.; Meyers, A. I.
J . Org. Chem. 1996, 61, 3362.
§ Current address: Department of Pharmacology, State University
of New York at Stony Brook, Stony Brook, NY 11794.
(1) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990. (b) Lown, W. J . In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1. (c) Tsuge,
O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231.
(2) (a) Ru¨ck-Braun, K.; Kunz, H. Chiral Auxiliaries in Cycloaddi-
tions; Wiley-VCH: Weinheim, 1999; pp 113-143. (b) Seyden-Penne,
J . Chiral Auxiliaries and Ligands in Asymmetric Synthesis; J ohn Wiley
and Sons: New York, 1995; pp 526-535. (c) Gothelf, K. V.; J ørgensen,
K. A. Chem. Rev. 1998, 98, 863.
(3) Pichon, M.; Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927
and references therein.
(4) For some leading references, see: (a) Tsuge, O.; Kanemasa, S.;
Yoshioka, M. J . Org. Chem. 1988, 53, 1384. (b) Kanemasa, S.; Yoshioka,
M.; Tsuge, O. Bull. Chem. Soc. J pn. 1989, 62, 869. (c) Kanemasa, S.;
Yamamoto, H. Tetrahedron Lett. 1990, 31, 3633. (d) Kanemasa, S.;
Uchida, O.; Wada, E. J . Org. Chem. 1990, 55, 4411.
(5) For some leading references, see: (a) Barr, D. A.; Grigg, R.; Nimal
Gunaratne, H. Q.; Kemp, J .; McMeekin, P.; Sridharan, V. Tetrahedron
1988, 44, 557. (b) Grigg, R.; Kemp, J .; Malone, J . F.; Rajviroongit, S.;
Tangthongkum, A. Tetrahedron 1988, 44, 5361. (c) Grigg, R. Tetra-
hedron: Asymmetry 1995, 6, 2475.
(6) Padwa A.; Chen, Y.-Y.; Chiacchio, U.; Dent, W. Tetrahedron
1985, 41, 3529.
(9) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817.
10.1021/jo010485p CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/05/2002

[3 + 2] Cycloaddition of N-Alkylidene Glycine Ester Anions
J . Org. Chem., Vol. 67, No. 3, 2002 649
Sch em e 1
The asymmetric synthesis of chiral nonracemic pro-
lines10 is currently attracting much attention due to the
interest to study conformational constraints into peptides
that influence their biological properties.11,12 In addition,
the synthesis of proline derivatives that selectively
incorporate the side chain functionality of other amino
acids (chimeras),10h,k,13 furnishing unique structural char-
acteristics to the original amino acid or to the peptide,
allows the analysis of their biological activity.11,12,13a In
this context, the kainoid amino acid family14 deserves
special mention as a group of nonproteinogenic pyrroli-
dine dicarboxylic acids that exhibit potent neuroexcita-
tory activity. This property is attributed to their action
as conformationally restricted analogues of the neuro-
transmitter glutamic acid.
Research in our group has been centered on the
synthesis of optically active compounds utilizing Fischer
alkenylcarbene complexes bearing (-)-8-phenylmenthol
as chiral auxiliary. We have demonstrated that these
compounds are excellent Michael acceptors when reacted
with alkyllithiums and lithium enolates, and that they
exhibited very high or total facial diastereoselectivity due
to the phenyl group hindrance of the chiral auxiliary on
the carbon-carbon double bond of the carbene complex.15
The Michael addition of chloro- or iodomethyllithium to
these chiral R,â-unsaturated carbene complexes, which
is followed by a ring closure to give cyclopropylcarbene
complexes with very high ee,15c can be considered as a
nucleophilic addition/ring closure (NARC)16 sequence for
the construction of [2 + 1] cycloadducts. Also, we have
shown their ability to act as dipolarophiles in [3 + 2]
cycloaddition reactions with diazomethane derivatives
and nitrilimines. ∆2-Pyrazolines were obtained from
these reactions in enantiomerically pure form.17 On the
other hand, we have recently reported the stereoselective
Michael addition of lithium enolates of N-(diphenyl-
methylidene)glycinate esters to chiral Fischer alkenyl-
carbene complexes.18 The Michael adducts were obtained
with high anti selectivity and high diastereofacial selec-
tivity. After oxidation of the metal carbene moiety and
hydrolysis of the resulting esters, enantiomerically en-
riched 3-substituted glutamic acids of unnatural stereo-
chemistry were obtained (Scheme 1). By contrast, the
same reaction with lithium enolates of N,N-dibenzyl-
glycinate esters, selectively furnished the corresponding
syn Michael adducts, which finally led to the synthesis
of natural enantiomerically enriched 3-substituted glutam-
ic acids (Scheme 1).
In the course of our investigations, we observed that
when the glycine ester was successively protected as an
aldimine, deprotonated, and added to a Fischer (()-
menthol-derived alkenylcarbene complex, the expected
open chain Michael adduct was not detected at all, and
instead a 2,4,5-trisubstituted-3-pyrrolidinylcarbene com-
plex was isolated as the only product in good yield and
(10) (a) Takano, S.; Moriya, M.; Iwabuchi, Y.; Ogasawara, K.
Tetrahedron Lett. 1989, 30, 3805. (b) Ezquerra, J .; Rubio, A.; Pedregal,
C.; Sanz, G.; Rodr´ıguez, J . H.; Garc´ıa-Ruano, J . L. Tetrahedron Lett.
1993, 34, 4989. (c) Langlois, N.; Rojas, A. Tetrahedron 1993, 49, 77.
(d) Panday, S. K.; Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett.
1994, 35, 6673. (e) Collado, I.; Ezquerra, J .; Vaquero, J . J .; Pedregal,
C. Tetrahedron Lett. 1994, 35, 8037. (f) Collado, I.; Ezquerra, J .;
Pedregal, C. J . Org. Chem. 1995, 60, 5011. (g) Mulzer, J .; Meier, A.;
Buschmann, J .; Luger, P. Synthesis 1996, 123. (h) Beausoleil, E.;
L’Archeveˆque, B.; Be´lec, L.; Atfani, M.; Lubell, W. D. J . Org. Chem.
1996, 61, 9447. (i) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.;
Potier, P. J . Org. Chem. 1997, 62, 765. (j) Lorthiois, E.; Marek, I.;
Normant, J .-F. Tetrahedron Lett. 1997, 38, 89. (k) Wang, H.; Germanas,
J . P. Synlett 1999, 33.
(11) (a) Hruby, V. J . Trends in Pharmacol. Sci. 1987, 8, 336. (b)
Purisiama, E.; Scheraga, H. J . Mol. Biol. 1987, 196, 697.
(12) (a) Stewart, D. E.; Sarkar, A.; Wampler, J . E. J . Mol. Biol. 1990,
214, 253. (b) Yaron, A.; Naider, F. Crit. Rev. Biochem. Mol. Biol. 1993,
28, 31.
(13) (a) Sharma, R.; Lubell, W. D. J . Org. Chem. 1996, 61, 202 and
references therein. (b) Langlois, N.; Rojas-Rousseau, A.; Decavallas,
O. Tetrahedron: Asymmetry 1996, 7, 1095. (c) Sabol, J . S.; Flynn, G.
A.; Friedrich, D.; Huber, E. W. Tetrahedron Lett. 1997, 38, 3687. (d)
Karoyan, P.; Chassaing, G. Tetrahedron Lett. 1997, 38, 85. (e) Wessig,
P. Synlett 1999, 1465.
(14) For some recent synthesis of R-kainic acid and kainoid amino
acid analogues, see: (a) Parsons, A. F. Tetrahedron 1996, 52, 4149
and references therein. (b) Hanessian, S.; Ninkovic, S. J . Org. Chem.
1996, 61, 5418. (c) Baldwin, J . E.; Fryer, A. M.; Spyvee, M. R.;
Whitehead, R. C.; Wood, M. E. Tetrahedron Lett. 1996, 37, 6293. (d)
Hashimoto, K.; Konno, K.; Shirahama, H. J . Org. Chem. 1996, 61, 4685.
(e) Bertrand, M.-P.; Gastaldi, S.; Nouguier, R. Tetrahedron Lett. 1996,
37, 1229. (f) Bachi, M. D.; Melman, A. J . Org. Chem. 1997, 62, 1896.
(g) Collado, I.; Ezquerra, J .; Mateo, A. I.; Rubio, A. J . Org. Chem. 1998,
63, 1995. (h) Cossy, J .; Cases, M.; Go´mez Pardo, D. Tetrahedron 1999,
55, 6153.
(15) (a) Barluenga, J .; Montserrat, J . M.; Flo´rez, J .; Garc´ıa-Granda,
S.; Mart´ın, E. Angew. Chem., Int. Ed. Engl. 1994, 33, 1392. (b)
Barluenga, J .; Montserrat, J . M.; Flo´rez, J .; Garc´ıa-Granda, S.; Mart´ın,
E. Chem. Eur. J . 1995, 1, 236. (c) Barluenga, J .; Bernad, P. L., J r.;
Concello´n, J . M.; Pin˜era-Nicola´s, A.; Garc´ıa-Granda, S. J . Org. Chem.
1997, 62, 6870.
(17) (a) Barluenga, J .; Ferna´ndez-Mar´ı, F.; Viado, A. L.; Aguilar,
E.; Olano, B. J . Chem. Soc., Perkin Trans 1 1997, 2267. (b) Barluenga,
J .; Ferna´ndez-Mar´ı, F.; Viado, A. L.; Aguilar, E.; Olano, B., Garc´ıa-
Granda, S.; Moya-Rubiera, C. Chem. Eur. J . 1999, 5, 883. (c) Bar-
luenga, J .; Ferna´ndez-Mar´ı, F.; Gonza´lez, R.; Aguilar, E.; Revelli, G.
A.; Viado, A. L.; Fan˜ana´s, F. J .; Olano, B. Eur J . Org. Chem. 2000,
1773. (d) Barluenga, J .; Ferna´ndez-Rodr´ıguez, M. A.; Aguilar, E.;
Ferna´ndez-Mar´ı, F.; Salinas, A.; Olano, B. Chem. Eur. J . 2001, 7, 3533
(corrigendum: Chem. Eur. J . 2001, 7, 4323). Alternatively, we have
described the formal [3 + 2] carbocyclization of Fischer alkenylcarbene
complexes to enamines and alkenyl oxazolines which involves the
coupling of the carbene complex as
a three carbon synthon: (e)
Barluenga, J .; Toma´s, M.; Ballesteros, A.; Santamar´ıa, J .; Brillet, C.;
Garc´ıa-Granda, S.; Pin˜era-Nicola´s, A.; Va´zquez, J . T. J . Am. Chem.
Soc. 1999, 121, 4516. (f) Barluenga, J .; Toma´s. M.; Sua´rez-Sobrino, A.
L. Synthesis 2000, 935.
(16) Fallon, G. D.; J ones, E. D.; Perlmutter, P.; Selajarern, W.
Tetrahedron Lett. 1999, 40, 7435 and references therein.
(18) Ezquerra, J .; Pedregal, C.; Merino, I.; Flo´rez, J .; Barluenga, J .;
Garc´ıa-Granda, S.; Llorca, M.-A. J . Org. Chem. 1999, 64, 6554.

650 J . Org. Chem., Vol. 67, No. 3, 2002
Merino et al.
Ta ble 1. [3 + 2] Cycloa d d u cts 3 of Lith iu m Glycin e En ola tes 2 a n d (()-Men th yl- a n d (-)-8-P h en ylm en th yloxy
Alk en ylca r ben e Com p lexes of Ch r om iu m 1 a n d Th eir Oxid a tion P r od u cts 4.
carbene
entry complex
glycine
anion
oxidation
methodd
R*
R1
Ph
Ph
2-furyl
R2
3a
yield (%)b
drc
4a
yield (%)e
drc
1
2
3
4
5
6
1a
1a
1b
1c
1c
1d
(()-menthyl
(()-menthyl
(()-menthyl
(-)-8-Ph-menthyl Ph
(-)-8-Ph-menthyl Ph
(-)-8-Ph-menthyl 2-furyl
2a
2b
2b
2a
2b
2b
t-Bu
Ph
Ph
t-Bu
Ph
Ph
3a
3b
3c
3d
3e
3f
89
86
87
78
75
99
90:10f 4a
85:15f 4b
A
75
73
83
62
53
65
88:6:6f,g
82:18f
92:8f,i
Ah
A
g99:1f
g99:1
96:4
4c
4d
4e
4f
B
85:11:4g
89:11k
92:8
Bj
Al
g99:1
a
b
c
Only the major diastereoisomer is shown. Isolated yield based on starting carbene complex 1. Diastereomeric ratio was determined
by 1H NMR at 300 or 200 MHz. Ratio shown corresponds to the syn (cis relative configuration at C2,C3): anti (trans relative configuration
at C2,C3) proportion. dMethod A: C5H5N+-O-, Et2O, rt. Method B: CAN, Me2CO/H2O, 0 °C to room temperature. Isolated yield based
e
on starting carbene complex 3. A mixture of two major and two minor isomers, each pair as a nearly equimolecular mixture. gIn this
f
oxidation reactions a small amount of a third diastereoisomer appeared. hOxidation through method B afforded 4b in 46% yield with
several minor isomers. iDetermined by 13C NMR spectroscopy (inverse gated decoupling experiment using 1 mg of chromium
acetylacetonate). jOxidation through method A gave 4e in 50% yield and 88:12 dr. kDetermined by 1H NMR at 400 MHz in C6D6. lOxidation
through method B gave 4f in 21% yield and 95:5 dr.
Sch em e 2a
selectivity (Scheme 1). It seemed that the enolate be-
haved this time as a formal azomethine ylide dipole and
the carbene complex acted as a formal dipolarophile,
giving rise to the corresponding [3 + 2] cycloadduct. We
envisioned this result as a way to prepare conforma-
tionally restricted â,γ-disubstituted glutamic acids in an
enantioselective fashion if chiral nonracemic alkenyl-
carbene complexes derived from (-)-8-phenylmenthol
were employed. We wish to describe here the results
obtained in the reaction of aldimine protected glycine
ester enolates with chiral chromium alkenylcarbene
complexes, as well as the manipulation of the reaction
products in order to obtain enantiomerically enriched
proline-glutamic acid chimeras.
Resu lts a n d Discu ssion
Dia ster eoselective F or m a l [3 + 2] Cycloa d d ition s
a
Conditions: (i) THF, -78 °C; (ii) silica gel; (iii) method A:
of Ald im in e Glycin e Ester En ola tes to Ch ir a l Ch r o-
C5H5N+-O-, Et2O. Method B: CAN, Me2CO, H2O.
m iu m Alk en ylca r b en e Com p lexes a n d Oxid a t ion
Rea ction s. Ethyl glycinate was treated with benzalde-
stereoselectivity yielding in two cases 3d ,f only one
hyde or pivalaldehyde to give the corresponding ald-
diastereoisomer (entries 4, 6) and almost a single dia-
imines, which were deprotonated with LDA in THF at
stereoisomer in the other case 3e (entry 5) as observed
-60 °C to give lithium enolates 2. When a THF solution
of racemic or enantiomerically pure alkenylcarbene com-
plex 1 was added dropwise to 2 at -78 °C an instant
reaction occurred that afforded syn,exo 3-pyrrolidinyl-
carbene complexes 3 after silica gel column chromatog-
raphy (Scheme 2, Table 1). These [3 + 2] cycloadducts 3
were isolated in good yields, with total regioselectivity
and very high stereoselectivity (syn refers to the relative
configuration at C2,C3,18 and exo denotes the relative
stereochemistry at C4,C519). The observed stereoselec-
tivity is very high, considering that four stereocenters
are created simultaneously and that diastereofacial
selectivity of the chiral alkene can double the stereo-
isomers. In fact, racemic carbene complexes 1a ,b derived
from (()-menthol did not show any facial diastereo-
selectivity and in each case, the major and the minor
cycloadducts 3a -c consisted of roughly a 1:1 mixture of
diastereoisomers (entries 1, 2, 3). However, the reactions
with chiral carbene complexes 1c,d derived from (-)-8-
phenylmenthol took place with very high facial dia-
by 1H and 13C NMR spectroscopy. Compounds 3 were
obtained exclusively as exo-cycloadducts. The minor
isomer detected in some reactions (entries 1, 2, 5)
corresponds to the epimeric isomer at the C2 carbon.
Consequently, dr in Table 1 refers to the syn (cis relative
configuration at C2,C3): anti (trans relative configuration
at C2,C3) ratio.18 In this sense, 2-furylvinyl carbene
complexes 1b,d showed better syn:anti selectivity in the
reaction than 2-phenylvinyl carbene complexes 1a ,c
(compare entries 3, 6 versus entries 2 and 5 respectively).
The elimination of the metal fragment from cyclo-
adducts 3 was effected through oxidation of these carbene
complexes to obtain the corresponding racemic 4a -c and
enantiomerically enriched 4d -f diesters. Oxidation with
pyridine N-oxide (method A) was carried out at room
temperature in ether as solvent. The reaction was slow,
mainly with carbene complexes derived from (-)-8-
phenylmenthol (entries 5, 6). In these long reaction times
(up to 7 days) partial decomposition of the carbene
complex may be competitive, which would account for the
commonly moderate chemical yields. The lower steric
demand of the menthol group compared to the (-)-8-
phenylmenthol group could be responsible for shorter
reaction times (2-3 days) with the racemic menthyl
derived carbene complexes and therefore better chemical
yields (entries 1, 2, 3). In addition, in both racemic and
(19) In the [3 + 2] cycloaddition between N-metalated azomethine
ylides and electron-deficient alkenes the exo,endo nomenclature has
been employed to denote respectively a trans and cis relationship
between the electron-withdrawing group at C4 coming from the alkene
and the substituent at the C5 position coming from the azomethine
ylide. See: Ayerbe, M.; Arrieta, A.; Coss´ıo, F. P.; Linden, A. J . Org.
Chem. 1998, 63, 1795.

[3 + 2] Cycloaddition of N-Alkylidene Glycine Ester Anions
J . Org. Chem., Vol. 67, No. 3, 2002 651
Ch a r t 1
chiral series of compounds, the ratio of diastereoisomers
in the starting carbene complex was not maintained after
the oxidation step. Indeed, a small loss in diastereo-
selectivity was observed. This effect had been previously
noted in the oxidation of the Michael adducts obtained
upon addition of N-diphenylmethylidene glycine esters
enolates to Fischer alkenylcarbene complexes18 and had
been attributed to partial epimerization of the labile
R-amino acid C2 carbon due to the free pyridine gener-
ated in the reaction medium and favored by long reaction
times. Other oxidants (DMSO, iodosobenzene) proved to
be unsuccessful. Only oxidation with ceric ammonium
nitrate (CAN, method B) was an alternative oxidation
method. The reactions were faster (3-12 h) but did not
significantly improve the previous results. Thus, in the
reaction of carbene complex 3b with CAN, a major
oxidation product within several minor diastereoisomeric
products were obtained; the major compound 4b was
isolated in 46% yield. Oxidation of carbene complex 3d
with CAN proceeded in good yield (62%), but the major
oxidation product was produced together with two minor
diastereoisomers (entry 4). This oxidation procedure
proved to be incompatible with the presence of a furyl
group on the starting carbene complex, since oxidation
of carbene complex 3f with CAN yielded only 21% of
product 4f, while oxidation of the same compound with
pyridine N-oxide increased the yield to 65% (entry 6). To
improve the results on the oxidation step, protection of
the amino group on carbene complexes 3 was accom-
plished. Thus, an N-acetyl pyrrolidinylcarbene complex
was prepared in 49% yield by quenching the reaction
between carbene complex 1a and enolate 2b with a small
excess of acetyl chloride. However, oxidation of this
N-protected carbene complex with pyridine N-oxide in
ether afforded the corresponding diester in similar
moderate 57% yield and with 81% de.
Structural elucidation of compounds 3 and 4 was based
on 1H and 13C NMR analysis of the reaction products.
The relative stereochemistry of the major diastereomeric
pyrrolidine derivative 3, 4 was determined as depicted
in Scheme 2 through analysis of NOE experiments on
the oxidation products 4d ,f. Irradiation of H4 on 4d
produced 5.8% NOE on the ortho protons of the phenyl
group at C3 establishing a trans relationship between
the substituents at C3 and C4. Irradiation on H3
produced 12.7% NOE on H2, while irradation of H5
produced 5.4% NOE on H2, which confirmed the cis
relationship of substituents at C2, C3, and C5 (Chart 1).
Further NOE experiments on proline ester 4f obtained
from enolate 2b led to similar results, determining the
cis relationship of the substituents at C2, C3, and C5 and
a trans disposition of the (-)-8-phenylmenthol-derived
ester with respect to the other three substituents (see
most significative NOE enhancements in Chart 1). Rela-
tive configuration of carbene complexes 3 and proline
esters 4a -c,e was assigned by analogy.
synthetic analogues,20 led us to ascertain the relative
configuration of 5b as the C2 epimer of 4b, since ∆δ )
δH2 (cisH2,H3) - δH2 (transH2,H3) > 0 (Chart 1).
The absolute stereochemistry of cycloadducts 3d -f and
4d -f was proposed to be (2S,3S,4R,5R) for 3-phenyl-
substituted pyrrolidines 3d ,e and 4d ,e and (2S,3R,4R,5R)
for 3-(2-furyl)-substituted proline derivatives 3f and 4f
(according to numbering in Scheme 2). This assignment
was based on the previous results obtained when the
reaction was carried out under the same conditions but
using a ketimine-protected glycine ester enolate.18 Ad-
dition of the lithium enolate of ethyl N-(diphenylmeth-
ylidene)glycinate to chiral alkenylcarbene complex 1d
afforded a Michael adduct, whose X-ray structure analy-
sis showed the R configuration for the carbon bearing
the 2-furyl group. The same sense of asymmetric induc-
tion had been previously observed upon addition of
different types of nucleophiles to chiral carbene com-
plexes 1c,d ,15 as well as in the [3 + 2] cycloaddition of
the same chiral carbene complexes with 1,3-dipoles.17
This facial selectivity can be interpreted by assuming
that in the most stable conformation of 1c,d , the phenyl
group on the chiral auxiliary shields the double bond
On the other hand, oxidation of a sample of carbene
complex 3b , consisting as a 1:1 mixture of diastereo-
isomers, allowed separation and characterization of both
the major syn,exo-4b and the minor anti,exo-5b isomers.
Analysis of the 1H NMR spectra of both compounds
reveals that the most significant difference is found in
the chemical shift and coupling constant of the H2
doublet signal (Chart 1). Applying to these compounds
the ∆δ empirical rule proposed for determining relative
stereochemistry of stereoisomeric mixtures of kainoid
(20) Although proline esters 4 and 5 do not belong to the kainoid
family, as glutamate subunit containing derivatives, they can be
considered esterified kainoid analogues. The ∆δ rule is applicable for
kainoid synthetic analogues and establishes that, when a pair of C2
epimers are available and their 1H NMR spectra are recorded in D2O
at the same or nearly equal pD, the H2 chemical shift of the H2,H3-
trans isomer appears at higher fields than that of the corresponding
H2, H3-cis isomer, irrespective of the C4 substituent. See ref 14d.

652 J . Org. Chem., Vol. 67, No. 3, 2002
Merino et al.
Ch a r t 2
Sch em e 3a
(Re,Re)-face of the alkene by π,π-orbital overlapping,21
inducing nucleophilic attack selectively from the back
(Si,Si)-face (Chart 1).
a
Mech a n istic P r op osa l. The obtention of cycloadducts
3 can be rationalized through a stepwise mechanism:
first addition of enolate 2 to the R,â-unsaturated carbene
complex 1 to give the corresponding syn Michael adduct,
followed by a 5-endo-trig ring closure in a NARC se-
quence. According to our previous results,18 the syn
diastereoselectivity observed in the first Michael addition
step can be explained in terms of the model A shown in
Chart 2. This model assumes an s-trans conformation for
the vinylcarbene complex and that the Michael addition
occurs with an anti relationship of the donor and acceptor
π-systems, placing the bulky substituent of the enolate
away from the (CO)5CrdC(OR*) group. In contrast to the
ketimine glycine ester enolate, the aldimine glycine ester
enolates react as a five-membered ring 1-oxaallyl anion18
furnishing syn anionic intermediate B, which in this case
undergoes subsequent ring closure presumably favored
by the higher reactivity and lower steric demand of the
aldimine carbon in relation to the analogous ketimine
center.22 Intramolecular imine addition of the carbene
complex enolate type anion to give the five-membered
ring would occur through approach topology C in which
H as the smallest substituent on the imine is placed in a
syn disposition with the bulky metal fragment to avoid
steric interactions. This arrangement would finally afford
cycloadducts 3 with the observed syn,exo stereochemistry.
Although the intramolecular imine addition step would
be a disfavored 5-endo-trig ring closure,23 there are
several literature precedents for this type of cyclization.24
Even in the related reaction of R,â-unsaturated esters
and azomethine ylides, a 5-endo-trig closure is proposed
to occur after an initial Michael nucleophilic addition in
order to explain the final products.5b
Conditions: (i) CF3CO2H, 12 N HCl, 150 °C; (ii) Me3SiCl,
MeOH, rt; (iii) Et3N, THF, rt; (iv) 2 N KOH, MeOH, 70 °C, (v)
HCl.
dipole and the R,â-unsaturated carbene complex 1 acting
as a dipolarophile. However, an alternative [3 + 2]
concerted mechanism would be improbable, since alkenyl-
carbene complexes 1 are highly π-deficient systems and
are most likely to behave as Michael acceptors rather
than dipolarophiles.19,25
Hyd r olysis Rea ction s. In the next step, pyrrolidine-
2,4-dicarboxylates 4, each as a pure diastereoisomer,26
were subjected to hydrolysis to remove the chiral auxil-
iary. Basic hydrolysis of 4b with 2 N KOH in refluxing
MeOH for 3 h occurred with concomitant partial epimer-
ization of the labile R-amino acid (C2) carbon resulting
in an 82:18 mixture of pyrrolidine-2,4-dicarboxylic acid
hydrochloride rac-8b and its 2-epimer rac-6b, respec-
tively (Scheme 3). When an acidic hydrolysis was under-
taken (TFA, 6 N HCl, 100 °C, 48 h), 1H NMR of the crude
hydrolysis product showed diacid rac-8b, but only in 29%
yield, with the balance being the corresponding carboxylic
acid containing unchanged the menthyl ester group. More
forcing conditions (TFA, 12 N HCl, 150 °C in a sealed
tube for 36 h) allowed complete hydrolysis but producing
total epimerization at the C2 center. Only one product,
1
diacid rac-6b was isolated in 75% yield, whose H NMR
revealed a trans relationship between the protons at C2
and C3. Confirmation of this structure was carried out
by subjecting a pure sample of the minor anti,exo
pyrrolidine 5b diastereoisomer to basic hydrolysis. In this
experiment, the same (identical NMR data) pyrrolidine-
2,4-dicarboxylic acid rac-6b was isolated in 52% yield
(Scheme 3).
The (-)-8-phenylmenthol derived ester 4e proved to
be more resistant to basic hydrolysis than the racemic
diester 4b. Treatment of pyrrolidine 4e with 3 N KOH
in MeOH under reflux for 16 h hydrolyzed both (-)-8-
phenylmenthyl and ethyl esters, but led to partial
epimerization of the labile C2 center. 1H NMR of the
From a formal point of view reaction products 3 might
be considered as the result of a [3 + 2] cycloaddition
between the enolate 2 acting as an azomethine ylide
(21) J ones, G. B.; Chapman, B. J . Synthesis 1995, 475.
(22) For a related precedent, see: Tatsukawa, A.; Dan, M.; Oh-
batake, M.; Kawatake, K.; Fukata, T.; Wada, E.; Kanemasa, S.; Kakei,
S. J . Org. Chem. 1993, 58, 4221.
(23) (a) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
(b) Baldwin, J . E.; Cutting, J .; Dupont, W.; Kruse, L. I.; Silberman,
L.; Thomas, R. C. J . Chem. Soc., Chem. Commun. 1976, 736.
(24) (a) Cookson, R. C.; Smith, S. A. J . Chem. Soc., Chem. Commun.
1979, 145. (b) Pelletier, S. W.; Mody, N. V. J . Am. Chem. Soc. 1979,
101, 492. (c) Gregory, B.; Bullock, E.; Chen, T.-S. J . Chem. Soc., Chem.
Commun. 1979, 1070.
(25) For a stepwise mechanism supported by theoretical studies,
see: Tatsukwa, A.; Kawakate, K.; Kanemasa, S.; Rudzinski, J . M. J .
Chem. Soc., Perkin Trans. 2 1994, 2525.
(26) Racemic derivatives are indeed an 1:1 mixture of diastereo-
isomers due to the menthyl group, but both diastereoisomers have
pyrrolidine rings with the same relative configuration.

[3 + 2] Cycloaddition of N-Alkylidene Glycine Ester Anions
J . Org. Chem., Vol. 67, No. 3, 2002 653
Con clu sion s
In summary, it has been demonstrated that chiral
nonracemic Fischer alkenylcarbene complexes bearing
(-)-8-phenylmenthol as chiral auxiliary undergo formal
[3 + 2] cycloaddition reactions with aldimine-protected
glycine ester enolates in a very high regio-, stereo-, and
enantioselective manner giving syn,exo-cycloadducts. This
methodology complements the related reaction between
chiral R,â-unsaturated esters5c,8b,c,d,e,h,j or amides8g and
N-metalated azomethine ylides, in which anti,endo-
cycloadducts are generally favored.28 The tetrasubstituted
pyrrolidine cycloadducts can be converted by successive
oxidation and hydrolysis, and depending on the hydroly-
sis conditions, into 4-carboxy trisubstituted prolines with
either natural or unnatural configuration at the amino
acid center. These systems can be considered as con-
strained analogues of â,γ-disubstituted glutamic acids
and could have potential application for understanding
the structures and properties of glutamate receptors.
F igu r e 1.
Sch em e 4a
Exp er im en ta l Section 29
Gen er a l P r oced u r e for th e Syn th esis of 3-P yr r olid in yl
Ca r ben e Com p lexes 3. All the operations were carried out
under a nitrogen atmosphere. LDA (1.6 equiv) was prepared
by adding n-BuLi (1.6 equiv) to a solution of i-Pr2NH (1.6
equiv) in THF at -60 °C. After being stirred for 15 min at
-60 °C, this LDA solution was cooled to -78 °C, and a solution
of the corrresponding ethyl N-alkylidene glycinate (1.6 equiv)
was added via an addition funnel. The resulting yellow-orange
solution was stirred for 30 min at -78 °C, and then a THF
solution of the corresponding R,â-unsaturated carbene complex
1 (1 equiv) was added dropwise from the addition funnel at
-78 °C. By the end of the addition step, the dark red starting
carbene complex solution had turned into a bright yellow one,
which was stirred for 1 h at -78 °C and then quenched with
silica gel at -78 °C for the adducts derived from phenylalkenyl
carbene complexes 1a ,c, or with a saturated NH4Cl aqueous
solution and silica gel at -78 °C for the adducts derived from
furylalkenyl carbene complexes 1b,d , and allowed to quickly
rise to room temperature. THF was evaporated under reduced
pressure, and the silica-adsorbed product was placed on top
of a column and purified by flash chromatography. Elution
with hexane/CH2Cl2, 9:1 removed some starting carbene
complex left and no polar materials. Sequential elution with
hexane/CH2Cl2, 4:1, 1:1 and hexane/CH2Cl2/EtOAc, 1:1:0.1
gave the pure carbene complexes 3 as one major diastereo-
isomer in the chiral examples 3d -f and as a mixture of two
major diastereoisomers in the racemic examples 3a -c due to
the stereocenters of racemic menthol.
a
Conditions: (i) LiOH, dioxane, H2O, 100 °C; (ii) HCl.
crude reaction product revealed a 1:1 mixture of hydroly-
sis product 8b and its 2-epimer diacid 6b in 62% yield.
Acidic hydrolysis of pyrrolidine 4e (TFA, 12 N HCl, 150
°C, 36 h) took place with total epimerization of the C2
center and proline hydrochloride 6b was isolated in 77%
yield (Scheme 3). Both racemic and chiral dicarboxylic
acids rac-6b and 6b were esterified to afford the corre-
sponding dimethyl diesters rac-7b and 7b. HPLC analy-
sis on a chiral support showed 90% ee for chiral proline
ester 7b. An NOE experiment on dimethyl diester 7b
showed the lack of the strong NOE between H2 and H3
existing in the cis proline esters 4d and 4f, as well as a
2.4% NOE between H2 and H4 and a 8.4% NOE between
H5 and H3. Irradiation on H2 also produced a 5.4% NOE
on the ortho protons of the phenyl group at C3 and 0.8%
NOE on the ortho protons of the phenyl group at C5, in
agreement with the proposed stereochemistry (Figure 1).
This acidic hydrolysis establishes a protocol for the
obtention of 4-carboxy-3,5-diphenylproline hydrochloride
6b with unnatural stereochemistry at the amino acid
center from pyrrolidine 4e.
On the other hand, treatment of 3-(2-furyl)-substituted
pyrrolidines 4c and 4f with LiOH in a 3:1 mixture of
dioxane/H2O at 100 °C for 6 and 16 h, respectively,
showed to be smooth enough to hydrolyze both (()-
menthyl and (-)-8-phenylmenthyl esters, while main-
taining the configuration at the C2 carbon (Scheme 4).
4-Carboxy-3-(2-furyl)-5-phenylproline hydrochlorides rac-
8c and 8c with natural stereochemistry at the amino acid
center were obtained in 43% and 37% yield, respec-
tively.27 Chiral electrophoresis analysis of these com-
pounds revealed that 8c was obtained with 96% ee. When
the hydrolysis reaction of 4c was carried out employing
THF instead of dioxane, the sterically hindered menthyl
ester did not react and only the ethyl ester was hydro-
lyzed.
P en ta ca r bon yl[1-[(2R,3R,4S,5S)-2-ter t-bu tyl-5-eth oxy-
car bon yl-4-ph en yl-3-pyr r olidin yl]-1-[(1R,2S,5R)-8-ph en yl-
m en th yloxy]m eth ylid en e]ch r om iu m (3d ). Ethyl N-(2,2-
dimethylpropylidene)glycinate (0.55 g, 3.2 mmol) in THF (8
mL) was treated with LDA prepared from i-Pr2NH (0.42 mL,
3.2 mmol) and n-BuLi (1.6 mL, 3.2 mmol) in THF (8 mL),
according to the general procedure. After 30 min at -78 °C, a
0.33 M THF solution of carbene complex 1c (6 mL, 2 mmol)
was diluted in THF (12 mL) and added to the glycinate solution
of 2a at -78 °C. The reaction mixture was stirred at - 78 °C
for 1 h and worked up as described above. Flash chromatog-
raphy of the crude product afforded 1.12 g (1.57 mmol, 78%
yield) of compound 3d as a yellow orangish solid in g99:1 dr:
mp 122-123 °C; Rf ) 0.55 (hexane/CH2Cl2 / EtOAc, 45:45:10);
1
[R]D ) +80.29 (c 1.01, CHCl3); H NMR (CDCl3, 300 MHz) δ
(28) For a few examples in which exo cycloadducts are obtained by
reaction of azomethine ylides and chiral acrylates, see ref 8a,f,i.
(29) General methods and preparation of carbene complexes 1 have
been recently published. See ref 18. Experimental procedures and
spectral data for compounds not described here are presented in the
Supporting Information.
(27) When these basic conditions were used to hydrolize pyrrolidine
4b partial epimerization of the C2 center was observed.

654 J . Org. Chem., Vol. 67, No. 3, 2002
Merino et al.
7.40-7.25 (10 H, m), 5.74 (1 H, dt, J ) 10.4, 4.3 Hz), 4.83 (1
H, dd, J ) 8.2, 4.7 Hz), 4.03 (1 H, dd, J ) 8.2, 9.5 Hz), 3.71-
3.54 (2 H, m), 3.46 (2 H, m), 2.48 (1 H, dt, J ) 12.7, 3.6 Hz),
2.38 (1 H, t, J ) 9.9 Hz, NH), 2.17 (1 H, bd, J ) 10.9 Hz),
1.70-1.52 (7 H, m + d, J ) 4.2 Hz), 1.52-1.15 (3 H, m), 1.15-
1.00 (10 H, m + s), 0.93-0.83 (4 H, m + d, J ) 6.4 Hz), 0.78
(3 H, t, J ) 7.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 360.8 (C),
222.1 (C), 215.8 (C), 170.0 (C), 149.5 (C), 140.9 (C), 128.7 (CH),
128.3 (CH), 128.1 (CH), 127.3 (CH), 125.8 (CH), 125.5 (CH),
94.8 (CH), 82.8 (CH), 72.7 (CH), 65.8 (CH), 60.3 (CH2), 52.5
(CH), 51.3 (CH), 44.3 (CH2), 40.8 (C), 33.7 (CH2), 33.3 (C), 32.1
(CH), 31.1 (CH3), 27.6 ((CH3)3), 27.5 (CH2), 21.9 (CH3), 21.6
(CH3), 13.5 (CH3); IR (film) ν (cm-1) 3329, 2058, 1940, 1741.
MS (EI) m/z 569 (M+ - 5CO, 1.7), 476 (4), 269 (15), 119 (100).
Anal. Calcd for C39H47CrNO8 (709.79): C, 66.00; H, 6.67; N,
1.97. Found: C, 66.15; H, 6.73; N, 2.00.
P e n t a ca r b on yl[1-[(2R ,3R ,4S ,5S )-5-e t h oxyca r b on yl-
2,4-d ip h e n yl-3-p yr r olid in yl]-1-[(1R ,2S ,5R )-8-p h e n yl-
m en th yloxy]m eth ylid en e]ch r om iu m (3e). Ethyl N-(phen-
ylmethylidene)glycinate (0.61 g, 3.2 mmol) in THF (8 mL) was
treated with LDA prepared from i-Pr2NH (0.42 mL, 3.2 mmol)
and n-BuLi (1.3 mL, 3.2 mmol) in THF (10 mL), according to
the general procedure. After 30 min at -78 °C, a 0.33 M THF
solution of carbene complex 1c (6 mL, 2 mmol) was diluted in
THF (12 mL) and added to the glycinate solution of 2b at -78
°C. The reaction mixture was stirred at - 78 °C for 1 h and
worked up as described above. Flash chromatography of the
crude product afforded 1.09 g (1.49 mmol, 75% yield) of
compound 3e as a yellow oil, in 96:4 dr: [R]D ) +51.8 (c 1.38,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.55 (2 H, d, J ) 7.1
Hz), 7.42-7.23 (13 H, m), 5.68 (1 H, dt J ) 10.4, 4.5 Hz), 5.30
(1 H, t, J ) 8.6 Hz), 4.29 (1 H, d, J ) 8.9 Hz), 4.20 (1 H, d, J
) 9.0 Hz), 3.88 (1 H, t, J ) 8.6 Hz), 3.76 (1 H, dd, J ) 10.7,
7.1 Hz), 3.62 (1 H, dd, J ) 10.7, 7.1 Hz), 2.59 (2 H, bm + dt,
J ) 12.3, 3.5 Hz), 2.01 (1 H, d, J ) 12.4 Hz), 1.61 (2 H, m),
1.48-1.34 (7 H, m + s), 1.25 (2 H, m), 0.94 (3 H, d, J ) 6.1
Hz), 0.88-0.74 (4 H, m + t, J ) 7.1 Hz); 13C NMR (CDCl3, 75
MHz) δ 364.3 (C), 222.7 (C), 215.0 (C), 171.4 (C), 149.7 (C),
139.4 (C), 128.8 (CH), 128.3 (CH), 127.6 (CH), 127.3 (CH),
125.8 (CH), 125.4 (CH), 125.1 (CH), 93.9 (CH), 87.5 (CH), 69.3
(CH), 66.1 (CH), 60.6 (CH2), 52.9 (CH), 51.1 (CH), 45.0 (CH2),
40.8 (C), 33.8 (CH2), 32.3 (CH), 31.1 (CH3), 27.2 (CH2), 22.5
(CH3), 21.5 (CH3), 13.3 (CH3); IR (film) ν (cm-1) 3337, 2060,
1936, 1736; MS (EI) m/z 589 (M+ - 5CO, 0.25), 131 (29), 119
(100), 91 (87). HRMS calcd for M+ - 5CO, C36H43CrNO3
589.2648, found 589.2637. Anal. Calcd for C41H43CrNO8
(729.78): C, 67.48; H, 5.93; N, 1.92. Found: C, 65.77; H, 5.98;
N, 1.92.
P en t a ca r b on yl[1-[(2R,3R,4R,5S)-5-et h oxyca r b on yl-4-
(2-fu r yl)-2-p h en yl-3-p yr r olid in yl]-1-[(1R,2S,5R)-8-p h en yl-
m en th yloxy]m eth ylid en e]ch r om iu m (3f). Ethyl N-(phen-
ylmethylidene)glycinate (0.61 g, 3.2 mmol) in THF (10 mL)
was treated with LDA prepared from i-Pr2NH (0.42 mL, 3.2
mmol) and n-BuLi (1.3 mL, 3.2 mmol) in THF (10 mL),
according to the general procedure. After 30 min at -78 °C, a
0.33 M THF solution of carbene complex 1d (6 mL, 2 mmol)
was diluted in THF (12 mL) and added to the glycinate solution
of 2b at -78 °C. The reaction mixture was stirred for 2 h and
worked up as described above. Flash chromatography of the
crude product afforded 1.42 g (1.97 mmol, 99% yield) of
compound 3e in g99:1 dr as a yellow oil which solidified after
cooling: mp 90-91 °C; Rf ) 0.52 (hexane/CH2Cl2 / EtOAc, 45:
45:10); [R]D ) +37.3 (c 1.17, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 7.51-7.26 (11 H, m), 6.28 (1 H, d, J ) 3.3 Hz), 6.13 (1
H, d, J ) 3.3 Hz), 5.64 (1 H, td, J ) 10.6, 4.7 Hz), 5.35 (1 H,
t, J ) 8.8 Hz), 4.16-4.04 (3 H, m), 3.83 (2 H, q, J ) 7.4 Hz),
2.80 (1 H, bs), 2.60 (1 H, m), 1.97 (1 H, bd, J ) 10.7 Hz), 1.60
(2 H, m), 1.58-1.20 (9 H, m), 1.10 (3 H, t, J ) 7.3 Hz), 1.10-
0.80 (4 H, m + d, J ) 6.2 Hz); 13C NMR (CDCl3, 75 MHz) δ
363.4 (C), 222.9 (C), 214.8 (C), 171.1 (C), 151.4 (C), 149.7 (C),
141.9 (CH), 139.1 (C), 128.8 (CH), 128.4 (CH), 128.2 (CH), 127.1
(CH), 125.8 (CH), 125.3 (CH), 110.2 (CH), 108.0 (CH), 93.7
(CH), 84.7 (CH), 69.6 (CH), 65.0 (CH), 61.1 (CH2), 50.9 (CH),
47.1 (CH), 45.0 (CH2), 40.6 (C), 33.8 (CH2), 30.9 (CH), 27.0
(CH2), 23.3 (CH3), 21.5 (CH3), 14.0 (CH3), 13.6 (CH3); IR (film)
ν (cm-1) 3340, 2060 1950, 1738. MS (EI) m/z 579 (M+- 5CO,
4), 328 (77), 191 (54), 119 (100), 105 (89). HRMS calcd for M+-
5CO, C34H41CrNO4 579.2441, found 579.2441. Anal. Calcd for
C
39H41CrNO9 (719.75): C, 65.08; H, 5.74; N, 1.94. Found: C,
64.97; H, 5.98; N, 1.94.
Gen er a l P r oced u r e for Oxid a tion of Ca r ben e Com -
p lexes 3. Meth od A. An Et2O solution of carbene complex 3
was treated with pyridine N-oxide (9-10 equiv) and stirred
for 48-72 h. At this point, if some starting carbene complex
still remained, as evidenced by TLC, the mixture was filtered
through Celite, and the resulting yellow solution was treated
again with pyridine N-oxide until disappearance of the carbene
complex. Then, the green reaction mixture was concentrated
under reduced pressure and the residue was taken up in
EtOAc and filtered through Celite. The yellow filtrate was
diluted 1:1 by volume with hexane, purged with air, and
subjected to air oxidation under direct sunlight or bulb light.
After 2-3 h, the resulting brown suspension was filtered
through Celite, and the filtrate was air oxidized again. These
operations were successively repeated, if necessary, until a
clear colorless solution was obtained (12-48 h). Solvent
removal on a rotary evaporator gave the crude products which
were purified by column chromatography. These compounds
were obtained as one major diastereoisomer in the chiral
examples 4d -f and as a roughly 1:1 mixture of two major
diastereoisomers in the racemic examples 4a -c.
Meth od B. Ceric ammonium nitrate (CAN, 4-5 equiv) was
dissolved in the minimun amount of water, and this solution
was added dropwise into an acetone solution of carbene
complex 3 via an addition funnel at -5-0 °C. Then, the cold
bath was removed, and the reaction was stirred for 3-24 h
until starting carbene complex disappeared as evidenced by
TLC. Solvents were evaporated, some water was added, and
the mixture was extracted with EtOAc twice. The organic layer
was washed with brine, dried over Na2SO4, and evaporated
to give the crude product, which was purified by column
chromatography.
2-Eth yl 4-[(1R,2S,5R)-8-P h en ylm en th yl] (2S,3S,4R,5R)-
5-ter t-Bu tyl-3-p h en ylp yr r olid in e-2,4-d ica r boxyla te (4d ).
Meth od B. A solution of carbene complex 3d (0.53 g, 0.75
mmol) in acetone (20 mL) was treated with CAN (2.05 g, 3.75
mmol) for 24 h according to the general procedure. Workup of
the reaction mixture as described above gave a crude product
which was purified by column chromatography (hexane/EtOAc,
4:1) to give 0.25 g (0.46 mmol, 62%) of 4d in 85:11:4 dr. Further
chromatographic purification allowed the isolation of pure
major diastereoisomer as a colorless oil: Rf ) 0.31 (hexane/
EtOAc, 4:1); [R]D ) +83.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 7.35-7.01 (10 H, m), 4.65 (1 H, dt, J ) 10.3, 3.9 Hz),
4.05 (1 H, d, J ) 8.6 Hz), 3.77-3.58 (2 H, m), 3.45 (1 H, t, J )
8.6 Hz), 3.35 (1 H, d, J ) 9.4 Hz), 2.44 (1 H, dd, J ) 9.2, 8.0
Hz), 2.22 (1 H, bs), 1.98-1.82 (2 H, m), 1.50 (2 H, m), 1.26 (4
H, s + m), 1.14 (4 H, s + m), 1.01 (10 H, m + s), 0.90-0.78 (4
H, m + d, J ) 6.4 Hz), 0.75 (3 H, t, J ) 7.3 Hz); 13C NMR
(CDCl3, 50 MHz) δ 173.4 (C), 171.8 (C), 151.0 (C), 139.9 (C),
128.1 (CH), 127.9 (CH), 127.7 (CH), 126.7 (CH), 125.0 (CH),
124.9 (CH), 75.6 (CH), 69.1 (CH), 64.5 (CH), 60.3 (CH2), 54.3
(CH), 52.1 (CH), 49.4 (CH), 40.8 (CH2), 39.5 (C), 34.3 (CH2),
33.0 (C), 31.0 (CH), 26.8 ((CH3)3), 26.6 (CH2), 26.5 (CH3), 26.4
(CH3), 21.6 (CH3), 13.4 (CH3); IR (film) ν (cm-1) 3342, 1724.
MS (EI) m/z 533 (M+, 1.8), 531 (7), 476 (M+-t-Bu, 88), 262 (66),
119 (74). HRMS calcd for C34H47NO4 533.3505, found 533.3471.
2-Eth yl 4-[(1R,2S,5R)-8-P h en ylm en th yl] (2S,3S,4R,5R)-
3,5-Dip h en ylp yr r olid in e-2,4-d ica r boxyla te (4e). Meth od
B. A solution of carbene complex 3e (0.95 g, 1.30 mmol) in
acetone (40 mL) was treated with CAN (3.85 g, 7.02 mmol)
for 3 h according to the general procedure. Workup of the
reaction mixture as described above gave a crude product
which was purified by column chromatography (hexane/EtOAc,
4:1, 2:1, 1:1) to give 0.38 g (0.63 mmol, 53%) of 4e in 89:11 dr.
Further chromatographic purification allowed the isolation of
pure major diastereoisomer as a colorless oil: Rf ) 0.34
1
(hexane/EtOAc, 4:1); [R]D ) +41.4 (c 0.49, CHCl3); H NMR
(C6D6, 400 MHz) δ 7.63 (2 H, d, J ) 6.9 Hz), 7.51-6.91 (13 H,
m), 4.60 (1 H, dt, J ) 9.9, 3.4 Hz) overlapped with 4.58 (1 H,

[3 + 2] Cycloaddition of N-Alkylidene Glycine Ester Anions
J . Org. Chem., Vol. 67, No. 3, 2002 655
d, J ) 9.9 Hz,), 4.22 (1 H, d, J ) 9.5 Hz), 3.86-3.70 (2 H, m +
dd, J ) 10.3, 7.3 Hz), 3.64 (1 H, dd, J ) 10.3, 7.3 Hz), 2.93 (1
H, t, J ) 10.3 Hz), 2.68 (1 H, bs), 1.70 (1 H, m), 1.59-1.25 (3
H, m), 1.02-0.86 (5 H, m + s), 0.85 (3 H, s), 0.85-0.6 (8 H,
m); 13C NMR (CDCl3, 75 MHz) δ 172.9 (C), 172.1 (C), 150.8
(C), 140.6 (C), 137.6 (C), 128.5 (CH), 128.4 (CH), 128.2 (CH),
127.9 (CH), 127.7 (CH), 127.2 (CH), 127.1 (CH), 125.6 (CH),
125.2 (CH), 124.9 (CH), 75.3 (CH), 65.4 (CH), 64.9 (CH), 60.6
(CH2), 57.3 (CH), 54.2 (CH), 50.0 (CH), 41.1 (CH2), 39.4 (C),
34.3 (CH2), 31.0 (CH), 26.6 (CH2), 26.5 (CH3), 25.6 (CH3), 21.5
(CH3), 13.4 (CH3); IR (film) ν (cm-1) 1722, 1454. MS (EI) m/z
553 (M+, 10.7), 338 (100), 266 (17), 220 (17). HRMS calcd for
mmol) in MeOH (5 mL) was treated with Me3SiCl (0.18 mL,
1.43 mmol) at room temperature under a nitrogen atmosphere
for 36 h. Solvents were evaporated under reduced pressure,
and THF (3 mL) was added to the residue followed by Et3N
(0.12 mL, 0.87 mmol). A solid appeared into the solution, and
the reaction mixture was stirred for 90 min. The solid was
filtered, and the filtrate was concentrated under reduced
pressure. Flash chromatography of the residue afforded 67 mg
(0.19 mmol, 69%) of the title compound as a colorless oil: [R]D
) -9.81 (c 0.53, CHCl3); Rf ) 0.31 (hexane/EtOAc, 3:1); 1H
NMR (CDCl3, 200 MHz) δ 7.38 (2 H, m), 7.30-7.16 (8 H, m),
4.56 (1 H, d, J ) 9.5 Hz), 4.02 (1 H, d, J ) 6.4 Hz), 3.75 (1 H,
dd, J ) 9.5, 6.7 Hz), 3.66 (3 H, s), 3.44 (3 H, s), 3.00 (1 H, t, J
) 9.5 Hz); 13C NMR (CDCl3, 50 MHz) δ 174.6 (C), 172.7 (C),
141.1 (C), 128.6 (CH), 128.3 (CH), 127.6 (CH), 127.2 (CH),
127.1 (CH), 126.6 (CH), 66.4 (CH), 65.9 (CH), 61.4 (CH), 53.4
(CH), 52.2 (CH3), 51.8 (CH3); IR (film) ν (cm-1) 3340, 1736.
MS (EI) m/z 339 (M+,12), 308 (9), 280 (M+ - CO2CH3, 100),
220 (50), 177 (26). HRMS calcd for C20H21NO4 339.1470, found
339.1468. Anal. Calcd for C20H21NO4 (339.39): C, 70.78; H,
6.23; N, 4.12. Found: C, 70.20; H, 6.35; N, 4.04.
(2S,3R,4R,5R)-3-(2-F u r yl)-5-p h en ylp yr r olid in e-2,4-d i-
ca r boxylic Acid Hyd r och lor id e (8c). To a solution of diester
4f (0.35 g, 0.64 mmol), in 24 mL of dioxane-water (3:1) was
added lithium hydroxide (0.11 g, 1.76 mmol), and the mixture
was refluxed for 16 h. The solvent was evaporated, and the
aqueous layer was extracted with EtOAc and then it was
acidified with 6 N HCl and cooled in an ice water bath. A white
solid (50 mg, 0.14 mmol) precipitated which was filtered and
dried under reduced pressure and characterized as the title
compound. Evaporation of the solvent afforded 30 mg (0.09
mmol) of the same product as a white solid (combined yield
37%). Data (including ee) were taken on the precipitated
compound: mp 272-273 °C; [R]D ) + 51.3 (c 0.11, H2O with
a drop of TFA); 1H NMR (DMSO-d6, 200 MHz) δ 7.65 (3 H,
m), 7.46 (3 H, m), 6.46 (1 H, m), 6.33 (1 H, m), 4.47 (1 H, d, J
) 9.9 Hz), 4.22 (1 H, d, J ) 8.8 Hz), 4.10 (1 H, t, J ) 8.9 Hz),
3.27 (1 H, t, J ) 9.8 Hz); 13C NMR (DMSO-d6, 50 MHz) δ 173.2
(C), 172.6 (C), 151.7 (CH), 142.3 (C), 140.5 (C), 128.4 (CH),
127.8 (CH), 127.3 (CH), 110.4 (CH), 107.0 (CH), 65.4 (CH), 62.8
(CH), 55.6 (CH), 46.0 (CH). MS (FAB) m/z 302 (M+ - Cl, 2),
301 (M+ - HCl, 8), 256 (M+ - HCl - CO2H, 19.5), 163 (97),
117 (100). HRMS calcd for C16H15NO5 (M+ - HCl) 301.0950,
found 301.0957.
C
36H43NO4 553.3192, found 553.3182. Anal. Calcd for C36H43-
NO4 (553.74): C, 78.08; H, 7.81; N, 2.52. Found: C, 77.27; H,
8.14; N, 2.61.
2-Eth yl 4-[(1R,2S,5R)-8-P h en ylm en th yl] (2S,3R,4R,5R)-
3-(2-F u r yl)-5-p h en ylp yr r olid in e-2,4-d ica r boxyla te (4f).
Meth od A. Carbene complex 3f (1.13 g, 1.57 mmol) and
pyridine N-oxide (0.96 g, 10.1 mmol) were allowed to react in
Et2O (70 mL) for 3 days. The suspension was filtered through
Celite, some more pyridine N-oxide (0.47 g, 5 mmol) was added,
and the reaction mixture was stirred at room temperature for
4 days. Then solvents were evaporated, and the residue was
air oxidized as described above. Flash chromatography of the
crude product (hexane/EtOAc, 4:1) afforded 0.40 g (1.0 mmol,
65% yield) of compound 4f as a colorless oil in 92:8 dr. Further
chromatographic purification allowed the isolation of pure
major diastereoisomer: Rf ) 0.34 (hexane/EtOAc, 4:1); [R]D
)
+40.6 (c 1.11, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.60 (2 H,
d, J ) 7.3 Hz), 7.39-7.03 (9 H, m), 6.28 (1 H, dd, J ) 3.0, 1.9
Hz), 6.09 (1 H, d, J ) 3.2 Hz), 4.65 (1 H, dt, J ) 10.6, 4.2 Hz),
4.47 (1 H, d, J ) 9.9 Hz), 4.18 (1 H, d, J ) 9.0 Hz), 4.03-3.85
(3 H, m), 3.03 (1 H, t, J ) 10.2 Hz), 2.65 (1 H, bs), 1.74 (2 H,
m), 1.46 (1 H, m), 1.36-1.16 (2 H, m), 1.06 (3 H, t, J ) 7.1
Hz), 0.98 (3H, s), 0.84 (4 H, m + s), 0.77 (5 H, m + d, J ) 6.5
Hz); 13C NMR (CDCl3, 75 MHz) δ 171.9 (C), 171.0 (C), 150.3
(C), 149.9 (C), 141.1 (CH), 139.2 (C), 127.9 (CH), 127.6 (CH),
127.3 (CH), 127.0 (CH), 126.5 (CH), 124.6 (CH), 124.2 (CH),
109.3 (CH), 106.7 (CH), 74.9 (CH), 65.3 (CH), 62.9 (CH), 60.4
(CH2), 55.5 (CH), 49.3 (CH), 47.2 (CH), 40.5 (CH2), 38.9 (C),
33.5 (CH2), 30.3 (CH), 26.7 (CH3), 26.1 (CH2), 24.1 (CH3), 20.8
(CH3), 13.0 (CH3); IR (film) ν (cm-1) 3367, 1724. MS (EI) m/z
543 (M+, 5), 476 (M+ - Fu, 57), 328 (77), 119 (100). HRMS
calcd for C34H41NO5 543.2984, found 543.2979.
(2R,3S,4R,5R)-3,5-Dip h en ylp yr r olid in e-2,4-d ica r b ox-
ylic Acid Hyd r och lor id e (6b). A solution of diester 4e (0.29
g, 0.52 mmol) in trifluoroacetic acid (0.5 mL) and 12 N HCl (4
mL) was heated at 150 °C in a pressure tube for 4 d. The
solution was cooled to room temperature, trifluoroacetic acid
was evaporated, and the mixture extracted with dichloro-
methane. The aqueous layer was evaporated to give the title
compound as a white solid (0.14 g, 0.40 mmol, 77%): mp 195-
196 °C; [R]D ) -21.06 (c 0.6, EtOH); 1H NMR (DMSO-d6, 200
MHz) δ 7.90-7.45 (14 H, m), 4.91 (1 H, d, J ) 10.5 Hz), 4.74
(1 H, d, J ) 9.3 Hz), 3.90 (1 H, apparent t, J ) 11.1, 10.9 Hz),
3.68 (1 H, apparent t, J ) 11.3, 10.5 Hz); 13C NMR (DMSO-
d6, 50 MHz) δ 171.2 (C), 169.4 (C), 137.3 (C), 132.1 (C), 129.7
(CH), 128.9 (CH), 128.7 (CH), 128.5 (CH), 128.2 (CH), 127.9
(CH), 65.6 (CH), 63.2 (CH), 57.3 (CH), 52.1 (CH). MS (FAB)
m/z 312 (M+ - Cl, 3), 311 (M+ - HCl, 10), 266 (M+-HCl - CO2H,
71), 220 (37), 163 (100). HRMS calcd for C18H17NO4 (M+ - HCl)
311.1157, found 311.1162.
Ack n ow led gm en t. This research was supported by
the Spanish FARMA III program (Ministerio de Indus-
tria) and the DGICYT (Grants PB-92-1005 and PB-97-
1271). S.L.Y.R. and I.M. thank the Ministerio de Edu-
cacio´n y Cultura for a postdoctoral fellowship and for a
research fellowship, respectively.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical and spectral data for ethyl N-(2,2-
dimethylpropylidene)glycinate, ethyl N-(phenylmethylidene)-
glycinate, compounds 3a -c, 4a -c, 5b, and rac-8b, and chart
with observed NOEs for compounds rac-7b and 8c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O010485P
Dieth yl (2R,3S,4R,5R)-3,5-Dip h en ylp yr r olid in e-2,4-d i-
ca r boxyla te (7b).30 A solution of compound 6b (100 mg, 0.28
(30) Brook, M. A.; Chan, T. A. Synthesis 1983, 201.