Stereoselective Michael addition of glycine anions to chiral fischer alkenylcarbene complexes. Asymmetric synthesis of β-substituted glutamic acids

Article abstract of DOI:10.1021/jo9819739

The reaction of lithium enolates of achiral N-protected glycine esters with chiral alkoxyalkenylcarbene complexes of chromium provided the corresponding Michael adducts with either high anti or syn selectivity depending on the nature of the nitrogen protecting group, and high diastereofacial selectivity when carbene complexes containing the (-)-8- phenylmenthyloxy group were employed. subsequent oxidation of the metal- carbene moiety followed by deprotection of the amine group and hydrolysis of both carboxylic esters afforded enantiomerically enriched 3-substituted glutamic acids of natural as well as unnatural stereochemistry. Alternatively, when the deprotection step was performed previously to the oxidation, cyclic aminocarbene complexes were formed, which finally led to optically active 3-substituted pyroglutamic acids.

Full text of DOI:10.1021/jo9819739

6554
J . Org. Chem. 1999, 64, 6554-6565
Ster eoselective Mich a el Ad d ition of Glycin e 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
â-Su bstitu ted Glu ta m ic Acid s
J esu´s Ezquerra and Concepcio´n Pedregal*
Centro de Investigacio´n Lilly, S. A. Avda de la Industria 30, Alcobendas, 28108 Madrid, Spain
Isabel Merino, 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
Santiago Garc´ıa-Granda† and Mar´ıa-Amparo Llorca†
Departamento de Quı´mica Fı´sica y Analı´tica, Facultad de Qu´ımica, Universidad de Oviedo,
J ulia´n Claverı´a 8, 33071 Oviedo, Spain
Received September 29, 1998 (Revised Manuscript Received April 7, 1999)
The reaction of lithium enolates of achiral N-protected glycine esters with chiral alkoxyalkenyl-
carbene complexes of chromium provided the corresponding Michael adducts with either high anti
or syn selectivity depending on the nature of the nitrogen protecting group, and high diastereofacial
selectivity when carbene complexes containing the (-)-8-phenylmenthyloxy group were employed.
Subsequent oxidation of the metal-carbene moiety followed by deprotection of the amine group
and hydrolysis of both carboxylic esters afforded enantiomerically enriched 3-substituted glutamic
acids of natural as well as unnatural stereochemistry. Alternatively, when the deprotection step
was performed previously to the oxidation, cyclic aminocarbene complexes were formed, which finally
led to optically active 3-substituted pyroglutamic acids.
In tr od u ction
derivatization of glycine esters is the formation of Schiff’s
bases with chiral ketones such as camphor6 or 2-hydroxy-
pinan-3-one,7 or the formation of a nickel(II) complex of
a Schiff base of glycine derived from a chiral ketone like
(S)-o-[N-(N-benzylprolyl)amino]benzophenone.8 In all these
approaches the source of chirality, to generate the
R-amino acid stereogenic center, is always present on the
glycinate anion synthon. However, it is possible to get
moderate to high enantioselectivity by alkylating di-
phenylmethyleneglycinate under phase-transfer catalysis
(PTC) using chiral tetralkylammonium chlorides as
catalysts.9
The development of new stereoselective strategies for
the synthesis of R-amino acids has evolved in a very
active field in recent years.1 Alkylation of glycine is one
of the most useful preparative routes to construct higher
R-amino acids. This requires the generation of the
enolate, derived from the suitable protected glycine
derivative, and its reaction with an electrophile to form
a new carbon-carbon bond. The construction of an
R-amino acid stereogenic center using this methodology
has been solved by incorporating chiral nonracemic
glycine synthons. Thus, the most classical ones include
Scho¨llkopf bislactim ethers,2 5,6-disubstituted N-acyl
oxazinones,3 2-(tert-butyl)-3-methyl-4-imidazolidinone,4 or
Oppolzer’s camphor sultam.5 An alternative asymmetric
The use of aldimines and ketimines derived from
glycine esters has become an easy way to prepare
(6) (a) McIntosh, J . M.; Leavitt, R. K.; Mishra, P.; Cassidy, K. C.;
Drake, J . E.; Chadha, R. J . Org. Chem. 1988, 53, 1947. (b) J iang, Y.-
Z.; Zhou, C.; Piao, H. Synth. Commun. 1989, 19, 881. (c) Kanemasa,
S.; Tatsukawa, A.; Wada, E. J . Org. Chem. 1991, 56, 2875. (d)
Tatsukawa, A.; Dan, M.; Ohbatake, M.; Kawatake, K.; Fukata, T.;
Wada, E.; Kanemasa, S.; Kakei, S. J . Org. Chem. 1993, 58, 4221.
(7) (a) El Achqar, A.; Boumzebra, M.; Roumestant, M.-L.; Viallefont,
P. Tetrahedron 1988, 44, 5319. (b) Solladie´-Cavallo, A.; Simon, M. C.
Tetrahedron Lett. 1989, 30, 6011. (c) El Hadrami, M.; Lavergne, J .-P.;
Viallefont, P.; Ait Itto, M. Y.; Hasnaoui, A. Tetrahedron Lett. 1991,
32, 3985. (d) Hoarau, S.; Fauche`re, J . L.; Pappalardo, L.; Roumestant,
M. L.; Viallefont, P. Tetrahedron: Asymmetry 1996, 7, 2585. (e)
Solladie´-Cavallo, A.; Koessler, J .-L.; Isarno, T.; Roche, D.; Andriami-
adanarivo, R. Synlett 1997, 217.
(8) (a) Belokon, Y. N.; Bulychev, A. G.; Ryzhov, M. G.; Vitt, S. V.;
Batsanov, A. S.; Struchkov, Y. T.; Bakhmutov, V. I.; Belikov, V. M. J .
Chem. Soc., Perkin Trans. 1 1986, 1865. (b) Soloshonok, V. A.; Avilov,
D. V.; Kukhar, V. P.; Meervelt, L. V.; Mischenko, N. Tetrahedron Lett.
1997, 38, 4903.
(9) (a) O’Donnell, M. J .; Bennett, W. D.; Wu, S. J . Am. Chem. Soc.
1989, 111, 2353. (b) Lipkowitz, K. B.; Cavanaugh, M. W.; Baker, R.;
O’Donnell, M. J . J . Org. Chem. 1991, 56, 5181. (c) O’Donnell, M. J .;
Wu, S. Tetrahedron: Asymmetry 1992, 3, 591. (d) Corey, E. J .; Xu, F.;
Noe, M. C. J . Am. Chem. Soc. 1997, 119, 12414. (e) Corey, E. J .; Noe,
M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
† X-ray analyses.
(1) (a) For a recent review, see: Duthaler, R. O. Tetrahedron 1994,
50, 1539. (b) Williams, R. M. Synthesis of Optically Active R-Amino
Acids; Pergamon: Oxford, 1989. (c) Coppola, G. M.; Schuster, H. F.
Asymmetric Synthesis. Construction of Chiral Molecules Using Amino
Acids; Wiley: New York, 1987.
(2) (a) Scho¨llkopf, U.; Pettig, D.; Busse, U.; Egert, E.; Dyrbusch, M.
Synthesis 1986, 737. (b) Williams, R. M. Aldrichim. Acta 1992, 25, 11.
(c) Hartzoulakis, B.; Gani, D. J . Chem. Soc., Perkin Trans. 1 1994,
2525.
(3) (a) Dellaria, J . F., J r.; Santarsiero, B. D. J . Org. Chem. 1989,
54, 3916. (b) Reno, D. S.; Lotz, B. T.; Miller, M. J . Tetrahedron Lett.
1990, 31, 827. (c) Williams, R. M.; Im, M.-N. J . Am. Chem. Soc. 1991,
113, 9276. (d) Baldwin, J . E.; Lee, V.; Schofield, C. J . Synlett 1992,
249.
(4) (a) Fitzi, R.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1986, 25,
345. (b) Seebach, D.; J uaristi, E.; Miller, D. D.; Schickli, C.; Weber, T.
Helv. Chim. Acta 1987, 70, 237. (c) Suzuki, K.; Seebach, D. Liebigs
Ann. Chem. 1992, 51. (d) Ezquerra, J .; Pedregal, C.; Mico´, I.; Na´jera,
C. Tetrahedron: Asymmetry 1994, 5, 921.
(5) (a) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
30, 6009. (b) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241. (c) J osien,
H.; Chassaing, G. Tetrahedron: Asymmetry 1992, 3, 1351.
10.1021/jo9819739 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/11/1999

Synthesis of â-Substituted Glutamic Acids
J . Org. Chem., Vol. 64, No. 18, 1999 6555
Sch em e 1
pioneering work by Casey and co-workers on conjugate
additions of phenyllithium, lithium diphenylcuprate,18
and enolate anions,19 some other carbon nucleophiles
have been 1,4-added to heteroatom-stabilized group 6
vinylcarbene complexes.20 More recent studies have
demonstrated that Michael addition of metal enolates to
alkoxy-21 or nitrogen-stabilized (O-chelated imidazoli-
dinone)22 Fischer alkenylcarbene complexes occurs with
syn diastereoselectivity irrespective of the enolate geom-
etry or the nature of the counterion. Furthermore, we
have described the first asymmetric Michael additions
of alkyllithiums, â-oxygen-substituted organolithium com-
pounds, and ketone or ester lithium enolates to enantio-
merically pure (-)-8-phenylmenthyloxy alkenylcarbene
complexes of chromium, which proceed with uniformly
high levels of asymmetric induction and high syn dia-
stereoselectivity when lithium enolates are involved.23
In this paper we report a novel approach for the
stereoselective synthesis of racemic and chiral â-substi-
tuted glutamic acids through the sequential Michael
addition of lithium enolates of achiral glycine esters to
chiral alkoxyalkenylcarbene complexes of chromium,
followed by oxidation of the metal-carbene moiety and
basic hydrolysis of the resulting diester. The initial 1,4-
addition takes place with either anti or syn selectivity
depending on the substitution pattern of the N-protected
glycine ester and occurs with high diastereofacial selec-
tivity when the enantiomerically pure above-mentioned
vinylcarbene complexes are used as Michael acceptors,
allowing, therefore, the asymmetric preparation of glutam-
ic acid derivatives of natural as well as unnatural
stereochemistry.
R-amino acids following the initial work of Stork et al.10
Since then, O’Donnell et al. have improved and developed
the method to reach maturity.11 Recently we have been
interested in the synthesis of unnatural amino acids
using the stable and commercially available ethyl N-
(diphenylmethylene)glycinate.12 The Michael addition
reaction of anions derived from this synthon to different
R,â-unsaturated esters showed a convenient means to
prepare glutamic acid derivatives.13 The preparation of
enantiomerically pure glutamic acid derivatives, by a
Michael addition reaction, can be achieved by two pos-
sible disconnection pathways of the C2-C3 bond as shown
in Scheme 1. While pathway A has been widely explored
using the chiral aforementioned glycine synthons,2-8
disconnection pathway B, where the source of chirality
resides on the Michael acceptor, has been much less
investigated. To our knowledge only three isolated ex-
amples of synthetic approach B have been reported, in
which ethyl (E)-3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]pro-
penoate,14 (4S)-3-[(E)-4′-bromo-4,4′-difluoro-2′-butenoyl]-
4-alkyl-2-oxazolidinone (alkyl ) benzyl, isopropyl),15 and
(R)-4-methylene-2-phenyloxazolidin-5-one or the corre-
sponding (S)-2-tert-butyl derivative16 are employed as
chiral Michael acceptors.17
It is well-recognized that Fischer alkenylcarbene com-
plexes behave as reactive Michael acceptors. Since the
Resu lts a n d Discu ssion
Ster eoselective Mich a el Ad d ition s of Glycin e
An ion s to (()-Men th yloxy a n d (-)-8-P h en ylm en -
th yloxy Alk en ylca r ben e Com p lexes. Lithium eno-
lates 2 and 3 were prepared by deprotonation of the
corresponding N-protected glycine ester with LDA in
THF at -78 °C. The results obtained in the reactions of
(10) Stork, G.; Leong, A. Y. W.; Touzin, A. M. J . Org. Chem. 1976,
41, 3491.
(11) (a) O’Donnell, M. J .; Boniece, J . M.; Earp, S. E. Tetrahedron
Lett. 1978, 2641. (b) O’Donnell, M. J .; Eckrich, T. M. Tetrahedron Lett.
1978, 4625. (c) Ghosez, L.; Antonie, J .-P.; Deffense, E.; Navarro, M.;
Libert, V.; O’Donnell, M. J .; Bruder, W. A.; Willey, K.; Wojciechowski,
K. Tetrahedron Lett. 1982, 23, 4255. (d) O’Donnell, M. J .; LeClef, B.;
Rusterholz, D. B.; Ghosez, L.; Antonie, J .-P.; Navarro, M. Tetrahedron
Lett. 1982, 23, 4259. (e) O’Donnell, M. J .; Bennett, W. D.; Bruder, W.
A.; J acobsen, W. N.; Knuth, K.; LeClef, B.; Polt, R. L.; Bordwell, F. G.;
Mrozack, S. R.; Cripe, T. A. J . Am. Chem. Soc. 1988, 110, 8520. (f)
O’Donnell, M. J .; Wu, S.; Huffman, J . C. Tetrahedron 1994, 50, 4507
and relevant references therein. For an application to solid-phase
synthesis of R,R-disubstituted amino acids and solid-phase unnatural
peptide synthesis, see: (g) O’Donnell, M. J .; Zhou, C.; Scott, W. L. J .
Am. Chem. Soc. 1996, 118, 6070. (h) Scott, W. L.; Zhou, C.; Fang, Z.;
O’Donnell, M. J . Tetrahedron Lett. 1997, 38, 3695.
(16) J avidan, A.; Schafer, K.; Pyne, S. G. Synlett 1997, 100.
(17) For other asymmetric syntheses of 3-substituted glutamic acid
derivatives through Michael addition of alkyllithiums or organocu-
prates to appropriately substituted chiral Michael acceptors, see: (a)
Yanagida, M.; Hashimoto, K.; Ishida, M.; Shinozaki, H.; Shirahama,
H. Tetrahedron Lett. 1989, 30, 3799. (b) J ako, I.; Uiber, P.; Mann, A.;
Wermuth, C.-G.; Boulanger, T.; Norberg, B.; Evrard, G.; Durant, F. J .
Org. Chem. 1991, 56, 5729. (c) Paz, M. M.; Sardina, F. J . J . Org. Chem.
1993, 58, 6990. (d) Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahe-
dron: Asymmetry 1994, 5, 351.
(12) (a) Ezquerra, J .; Pedregal, C.; Moreno-Man˜as, M.; Pleixats, R.;
Roglans, A. Tetrahedron Lett. 1993, 34, 8535. (b) Mazo´n, A.; Na´jera,
C.; Ezquerra, J .; Pedregal, C. Tetrahedron Lett. 1995, 36, 7697. (c)
Mazo´n, A.; Na´jera, C.; Ezquerra, J .; Pedregal, C. Tetrahedron Lett.
1997, 38, 2167.
(18) Casey, C. P.; Brunsvold, W. R. J . Organomet. Chem. 1974, 77,
345.
(19) Casey, C. P.; Brunsvold, W. R. Inorg. Chem. 1977, 16, 391.
(20) Enolate type carbene complex anions: (a) Macomber, D. W.;
Hung, M.-H.; Verma, A. G.; Rogers, R. D. Organometallics 1988, 7,
2072. (b) Macomber, D. W.; Hung, M.-H.; Madhukar, P.; Liang, M.;
Rogers, R. D. Organometallics 1991, 10, 737. (c) Macomber, D. W.;
Madhukar, P.; Rogers, R. D. Organometallics 1991, 10, 2121. â-Oxygen-
substituted organolithium compounds: (d) Barluenga, J .; Montserrat,
J . M.; Flo´rez, J . J . Chem. Soc., Chem. Commun. 1993, 1068. Halo-
methyllithium compounds: (e) Barluenga, J .; Bernad, P. L., J r.;
Concello´n, J . M. Tetrahedron Lett. 1995, 36, 3937. (f) 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.
(13) Racemic synthesis: (a) Yamaguchi, M.; Torisu, K.; Minami, T.
Chem. Lett. 1990, 377. (b) Kanemasa, S.; Uchida, O.; Wada, E. J . Org.
Chem. 1990, 55, 4411. (c) Rubio, A.; Ezquerra, J . Tetrahedron Lett.
1995, 36, 5823. (d) Lo´pez, A.; Moreno-Man˜as, M.; Pleixats, R.; Roglans,
A.; Ezquerra, J .; Pedregal, C. Tetrahedron 1996, 52, 8365. (e) Antolini,
L.; Forni, A.; Moretti, I.; Prati, F.; Laurent, E.; Gestmann, D.
Tetrahedron: Asymmetry 1996, 7, 3309. Reactions with N-[bis(meth-
ylthio)methylene]glycinates: (f) Alvarez-Ibarra, C.; Csa´ky¨, A. G.;
Maroto, M.; Quiroga, M. L. J . Org. Chem. 1995, 60, 6700. (g) Alvarez-
Ibarra, C.; Csa´ky¨, A. G.; Lo´pez de Silanes, I.; Quiroga, M. L. J . Org.
Chem. 1997, 62, 479. (h) Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Mart´ın
Ortega, E.; de la Morena, M. J .; Quiroga, M. L. Tetrahedron Lett. 1997,
38, 4501.
(21) (a) Aoki, S.; Fujimura, T.; Nakamura, E. J . Am. Chem. Soc.
1992, 114, 2985. (b) Nakamura, E.; Tanaka, K.; Fujimura, T.; Aoki,
S.; Williard, P. G. J . Am. Chem. Soc. 1993, 115, 9015.
(14) For a unique experiment see ref 6d.
(22) Shi, Y.; Wulff, W. D. J . Org. Chem. 1994, 59, 5122.
(15) (a) Shibuya, A.; Kurishita. M.; Ago, C.; Taguchi, T. Tetrahedron
1996, 52, 271. For correction of the absolute stereochemistry reported
in this paper, see: (b) Shibuya, A.; Sato, A.; Taguchi, T. Bioorg. Med.
Chem. Lett. 1998, 8, 1979.
(23) (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.

6556 J . Org. Chem., Vol. 64, No. 18, 1999
Ezquerra et al.
Ta ble 1. Mich a el Ad d ition s of Lith iu m Glycin e En ola tes to (()-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
carbene
complex
glycine
anion
drc
anti:syn
entry
R*
R1
Ph
Ph
2-furyl
Bu
t-Bu
Ph
Ph
2-furyl
3-furyl
Ph
R2
Et
t-Bu
Et
Et
Et
Et
t-Bu
Et
Et
Et
R3
R4
producta
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1b
1c
1d
1e
1e
1f
1g
1a
1a
1a
1e
1e
(()-menthyl
2a
2b
2a
2a
2a
2a
2b
2a
2a
3a
3b
3c
3a
3b
4a
4b
4c
4d
4e
4f
4g
4h
4i
5j
5k
5l
5m
5n
78
79
80
62
30
65
87
69
89
86
83
14
86
80
80:20d,e
82:18d
75:25d
50:50f
50:50f
96:4
(()-menthyl
(()-menthyl
(()-menthyl
(()-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
(()-menthyl
80:20
91:9e
97:3
PhCH2
PhCH2
Me2Si(CH2)2SiMe2
PhCH2
PhCH2
PhCH2
PhCH2
10:90d
8:92d
(()-menthyl
(()-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
Ph
Ph
Ph
Ph
t-Bu
Et
Et
0:100
10:90
13:87
PhCH2
PhCH2
t-Bu
a
b
Only the major diastereoisomer is shown. Isolated yield based on the corresponding carbene complex 1. c Diastereomeric ratio was
determined by 1H NMR at 300 or 200 MHz. A mixture of two major and two minor isomers, each pair as a nearly equimolecular mixture.
d
The ratio shown corresponds to the anti/syn diastereoselectivity. e Determined by 13C NMR spectroscopy (inverse gated decoupling
experiments using 1 mg of chromium acetylacetonate). f A roughly equimolecular mixture of four diastereoisomers was formed.
Sch em e 2a
with the same Michael acceptors 1a ,e under identical
experimental conditions led with high selectivity to the
initially expected syn Michael adducts 5 (Table 1, entries
10-14). The highest selectivity was achieved with the
enolate of the stabase33 adduct of ethyl glycinate 3c. This
reaction provided a single diastereoisomer but unfortu-
nately with a very low chemical yield to be synthetically
useful (Table 1, entry 12). The assignment of either syn
(Table 1, entries 6-9) or anti (Table 1, entries 13 and
14) stereochemistry to the minor diastereoisomers formed
in the reactions with (-)-8-phenylmenthyloxy carbene
complexes 1e-g has not been confirmed, since these
compounds were never isolated in pure form. The pos-
sibility that these minor products could be in each case
the other diastereomeric anti or syn adduct cannot be
ruled out.
a
Conditions: (i) THF, -78 °C; (ii) silica gel.
The stereochemical assignment was made in the case
of anti adducts 4 from a single-crystal X-ray structure
determination carried out with enantiomerically pure
compound 4h .24 This analysis unambiguously established
the relative configuration as depicted in Scheme 2 and
confirmed the drawn absolute configuration of the newly
created stereogenic centers, which is in agreement with
the sense of facial selectivity previously observed in other
conjugate additions to (-)-8-phenylmenthyloxy alkenyl-
carbene complexes of chromium.20f,23 The relative syn
stereochemistry of adducts 5 was determined by the
chemical transformation of carbene complex 5j to tet-
rahydropyran 8 as shown in Scheme 3. This sequence
involves initial oxidation of the chromium complex 5j
(used as a syn/anti, 90:10, mixture) to ester 6j followed
by procedures previously described for analogous struc-
tures.25 Purification of the major diastereoisomer led to
compound 8. The coupling between the nonaromatic
methine protons of this six-membered ring cyclic struc-
ture 8 (J H3,H4 ) 11.4 Hz) corresponds to a trans orienta-
tion of the phenyl and N,N-dibenzylamino groups. For
these glycine anions with racemic or enantiomerically
pure vinylcarbene complexes 1 are summarized in Scheme
2 and Table 1. We observed that treatment of carbene
complexes 1 with lithium enolates of benzophenone Schiff
base derivatives of glycine alkyl esters 2 at -78 °C led
to a rapid reaction (1-3 h) which afforded, after silica
gel column chromatography, the corresponding and
unexpected anti Michael adduct 4. The anti/syn dia-
stereoselectivity of this conjugate addition was good when
3-aryl-substituted carbene complexes 1a (R1 ) Ph) and
1b (R1 ) 2-furyl) were used as acceptors (Table 1, entries
1-3), while with aliphatic carbene complexes 1c (R1 )
Bu) and 1d (R1 ) t-Bu) the chemical yield was lower, no
selectivity was observed, and a nearly equimolecular
mixture of the four possible isomers was formed (Table
1, entries 4 and 5); in addition adducts 4d ,e were
unstable and difficult to purify. These racemic complexes
1a -d derived from (()-menthol did not show any facial
selectivity; in each case the major (anti) and the minor
(syn) adducts were formed as a roughly 1:1 mixture of
isomers. However, these conjugate addition reactions
with chiral carbene complexes 1e-g derived from (-)-
8-phenylmenthol took place with high anti and facial
selectivity, yielding as very major isomers adducts 4f-i,
each one observed by 1H and 13C NMR as almost a single
diastereoisomer (Table 1, entries 6-9). On the other
hand, the reactions of lithium enolates of N,N-dibenzyl-
glycinates esters 3a ,b or N,N-disilylated glycine ester 3c
(24) Crystal data for 4h : C45H45CrNO9, red crystal, size 0.20 × 0.20
× 0.20 mm, Mr ) 795.82, orthorhombic, space group P212121, a )
14.164(3) Å, b ) 14.981(6) Å, c ) 19.904(7) Å, V ) 4223(2) Å3, Z ) 4,
Dx ) 1.252 g/cm3, µ ) 3.26 cm-1, F(000) ) 1672, T ) 293(2) K; final
conventional R ) 0.050 for 2642 “observed” reflections and wR2 ) 0.161
(for all reflections) and 513 variables; GOF ) 0.974; Flack’s parameter
ø ) 0.05(4). Full details are available in the Supporting Information.
(25) Yamaguchi, M.; Tsukamoto, M.; Tanaka, S.; Hirao, I. Tetrahe-
dron Lett. 1984, 25, 5661.

Synthesis of â-Substituted Glutamic Acids
J . Org. Chem., Vol. 64, No. 18, 1999 6557
bered ring derivative B.13a Arrangement A could be
favored by the stability provided by the two phenyl
groups and the six-membered ring intramolecular coor-
dination. Thus, approach topology D in which the CO2R2
group is placed away from the metal-carbene moiety
explains the formation of anti Michael adducts 4.26
However, the possibility that these later reactions are
under thermodynamic rather than kinetic control, and
so proceed with syn selectivity followed by epimerization
at C2, cannot be entirely eliminated. That epimerization
would be a consequence of the greater acidity of the
hydrogen bonded to C2 in compounds 4 compared to
adducts 5. Finally, the sense of chirality of the products
derived from (-)-8-phenylmenthyloxy carbene complexes
follows from the known model F of the most stable
conformation of these complexes, which is favored by the
alkene-arene π-stacking effect.27 Nucleophile attack on
these Michael acceptors occurs selectively from the
opposite side of the phenyl group.20f,23
Sch em e 3
Ch a r t 1
Oxid a tion of Mich a el Ad d u cts 4 a n d 5. In the next
step carbene complexes 4 and 5 were transformed to the
corresponding carboxylic ester 6, 9, or 10 by oxidation of
the metal-carbene functional group. The results are
gathered in Table 2. Oxidative removal of the pentacar-
bonylchromium fragment was mainly effected with pyr-
idine N-oxide using either THF or ether as solvent. This
oxidation proved to be a slow reaction (reaction time
between 2 and 5 days), probably because of steric
inhibition imposed by the (()-menthyl or (-)-8-phenyl-
menthyl group, and under these conditions partial de-
composition of the starting carbene complex might be-
come competitive, which could account for the commonly
moderate chemical yields. Oxidation of racemic 4a -c and
chiral 4f-i anti Michael adducts with pyridine N-oxide
in THF (method A) or Et2O (method C) led to the
corresponding anti imino ester 9a -c,f-i. In the case of
the chiral compounds 9f-i the reaction proceeded uni-
formly, maintaining the diastereomeric ratio of the
corresponding starting material (Table 2, entries 6-10).
On the other hand, in the oxidation reactions carried out
with racemic products 4a -c, the anti/syn diastereomeric
ratio of imino esters 9a -c seems to be dependent on the
reaction conditions of time, temperature, and amount of
oxidant (Table 2, entries 1 and 3-5). In both racemic and
chiral sets of compounds, the reactions in ether, where
pyridine N-oxide is less soluble, were slower than in THF,
and in addition the anti/syn ratio of diastereoisomers
when Et2O is used as solvent can be significantly lower
(Table 2, entries 1, 4, and 6 versus 3, 5, and 7, respec-
tively). These lower selectivities could be explained as a
result of partial epimerization at the amino acid (C2)
center, which would be induced by the free pyridine
generated in the reaction medium and favored at pro-
longed reaction times. Racemic 5j and chiral 5m syn
Michael adducts were likewise oxidized with pyridine
N-oxide in ether, affording the corresponding syn amino
ester 6j,m with high selectivity and in these cases high
chemical yield as well (Table 2, entries 11 and 12). Ceric
the remaining compounds 4 and 5, the configurations
have been assumed by analogy.
The syn/anti diastereoselectivity of these conjugate
additions, which proved to be strongly dependent on the
nature of the protective group on the glycine nitrogen
atom, can be rationalized in terms of the model shown
in Chart 1. This model was initially proposed by Naka-
mura et al.21b to explain the diastereoselective syn
Michael addition of ketone and ester metal enolates to
heteroatom-stabilized Fischer vinylcarbene complexes,
which thus far seemed to be a general property.22,23 This
open chain 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 bulkiest substituent of the enolate
away from the (CO)5CrdC(OR*) grouping to avoid steric
interactions. According to that, the formation of syn
Michael adducts 5 can be explained by the sterically
favorable approach E of anion 3 as a (Z)-enolate (1-
oxaallylanion C) in which the R3R4N group is placed away
from the metal-carbene moiety. The diastereoselective
anti Michael additions observed with lithium enolates 2
could be explained likewise by this mechanistic model
but assuming that this type of enolate interacts with the
vinylcarbene complex as a 2-azaallylanion six-membered
ring structure A instead of 1-oxaallylanion five-mem-
(26) Either anti (see refs 2a, 6c,d, 13e,f, and 15a) or syn (see refs 4c
and 13a) selective Michael additions of glycine synthon anions to
different R,â-unsaturated esters have been previously observed. As
indicated in ref 13a these opposite results could be related with the
structure of the glycine enolate reacting either as a 2-azaallylanion,
which led to the anti adduct, or as an 1-oxaallylanion leading to the
syn adduct when no possibility of formation of the 2-azaallylanion
structure exists.
(27) J ones, G. B.; Chapman, B. J . Synthesis 1995, 475.

6558 J . Org. Chem., Vol. 64, No. 18, 1999
Ta ble 2. Oxid a tion of Ca r ben e Com p lexes 4 a n d 5. Obten tion of P r od u cts 6, 9, a n d 10
Ezquerra et al.
starting
complex
oxidation
methoda
drd
anti:syn
entry
R*
R1
Ph
Ph
Ph
2-furyl
2-furyl
Ph
Ph
Ph
R2
Et
Et
t-Bu
Et
Et
Et
Et
t-Bu
Et
productb
yield(%)c
1
2
3
4
5
6
7
8
9
4a
4a
4b
4c
4c
4f
A
B
C
A
C
A
C
A
A
A
C
C
(()-menthyl
9a
10a
9be
9c
9c
9f
76
50
70
69
65
71
64
60
56
52
92
59
62:38
14:86
47:53f
74:26
67:33
92:8
87:13
80:20g
92:8h
100:0
13:87
5:95
(()-menthyl
(()-menthyl
(()-menthyl
(()-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
(-)-8-Ph-menthyl
(()-menthyl
4f
9f
4g
4h
4i
5j
5m
9g
9h
9i
6j
6m
2-furyl
3-furyl
Ph
10
11
12
Et
Et
Et
(-)-8-Ph-menthyl
Ph
a
b
Method A: C5H5N+-O-, THF, rt. Method B: CAN, Me2CO/H2O, 0 °C to rt. Method C: C5H5N+-O-, Et2O, rt. Only the major
diastereoisomer is shown. c Isolated yield based on the corresponding carbene complex 4 or 5. Diastereomeric ratio was determined by
d
1H NMR spectroscopy. e Almost a 1:1 mixture of 9b and its corresponding syn diastereoisomer was formed in this case. f The reaction was
refluxed for 6 h after 4 d at rt. Determined by 13C NMR spectroscopy. In this case a 2:1 mixture of THF/Et2O was used as solvent and
g
h
the reaction was refluxed for 25 h.
Sch em e 4a
methine hydrogens (J H2,H3 ) 4.6 Hz) corresponds to a
trans orientation7a,28 of both hydrogen atoms in com-
pounds 12a and rac-12a . The stereochemistry of com-
pound 10a was established after transformation of this
syn amino diester to the corresponding racemic R-amino
acid rac-16a (rac-14a , 95%; rac-16a , 44%), and compari-
son of its NMR spectral data with those previously
described for (2S,3S)-3-phenylglutamic acid.8a This trans-
formation was effected following the procedure shown in
the next section and Scheme 5 for this same product (10a )
but generated in a different way.
Hyd r olysis Rea ction s. Syn th esis of 3-Su bstitu ted
Glu ta m ic Acid s (Sch em e 5). Finally, the syn amino
and anti imino diesters 6 and 9, respectively, were
converted to the corresponding â-substituted glutamic
acids by first removing the protective group on the
nitrogen atom and then hydrolysis of the carboxylic
esters. Thus, catalytic hydrogenation in the presence of
palladium on carbon of N,N-dibenzyl derivatives 6j,m
furnished syn amino diesters 10a ,f respectively, which
were further refluxed with 2 N KOH in methanol. After
acidification with concentrated HCl the corresponding
hydrochloride derivative of syn 3-phenylglutamic acid
rac-14a or 14a was isolated. Treatment of these deriva-
tives with propylene oxide in methanol allowed the
liberation of (2S,3S)-3-phenylglutamic acid as optically
active 16a or racemic rac-16a product, whose physical
and spectral properties are in agreement with those
previously reported.8a On the other hand, hydrolysis of
the benzophenone imine group of compounds 9b,f,g,i was
effected with 5 N hydrochloric acid at room temperature.
In this way, the corresponding anti amino diesters were
isolated either directly as their hydrochloride derivatives
in the case of 19b,f,g or as the free amino diester 11i by
subsequent extraction of the reaction mixture under basic
conditions. Hydrolysis of diesters 19b,f,g and 11i was
carried out following two different reaction sequences
depending on the nature of the R2 group. The tert-butyl
derivatives 19b,g (R2 ) t-Bu) were first treated with
a
Reagents: (i) NH2OH‚HCl, NaOAc, EtOH, reflux.
ammonium nitrate (CAN) can also be used as oxidizing
agent, which removes the metal fragment at a higher
reaction rate but provided the corresponding ester with
lower chemical yield. Thus, the reaction of anti carbene
complex 4a with CAN was completed in 1 h, affording
syn amino ester 10a with 72% de (Table 2, entry 2). This
result indicates that under these oxidation conditions
epimerization at the R-amino acid center (C2 carbon) and
hydrolysis of the benzophenone imine concurrently took
place. Other oxidants, including DMSO tested with
compound 4i, oxone, or iodosobenzene both experimented
with carbene complex 4h , were unsuccessful, leading to
even much lower chemical yields or mostly to an uni-
dentified mixture of products.
The anti relative configuration assigned to oxidation
products 9 was confirmed in two cases by conversion of
imino esters 9a ,f, used as diastereomerically pure major
(anti) isomers, to cyclic lactams rac-12a and 12a as
detailed in Scheme 4. Cleavage of the imine was per-
formed with hydroxylamine hydrochloride and sodium
acetate in ethanol at reflux.6c Under these conditions
racemic compound 9a led to a mixture of 11a and its
cyclized product rac-12a that were readily separated by
column chromatography. Chiral derivative 9f, bearing a
bulkier chiral auxiliary, afforded after heating for 3 h
amino diester 11f as a single product; partial cyclization
of 11f to 12a was observed at longer reaction time and
with an excess of in situ generated hydroxylamine
acetate. The coupling between the five-membered ring
(28) (a) Mauger, A. B. J . Org. Chem. 1981, 46, 1032. (b) Hartwig,
W.; Born, L. J . Org. Chem. 1987, 52, 4352.

Synthesis of â-Substituted Glutamic Acids
J . Org. Chem., Vol. 64, No. 18, 1999 6559
Sch em e 5a
a
Key: (i) 5 N HCl, THF, rt. Sequence A: (ii) CF3CO2H, CH2Cl2, rt; (iii) 2 N KOH, MeOH, reflux; (iv) HCl. Sequence B: (iii); (iv). (v)
Propylene oxide, MeOH, rt or Dowex. b Anti/syn ratio. c Isolated as amino diester 11i instead of its hydrochloride 19i by extraction under
basic conditions.
Sch em e 6a
trifluoroacetic acid at room temperature and then with
2 N potassium hydroxide in methanol at reflux, whereas
the ethyl derivatives 19f and 11i (R2 ) Et) were directly
saponified (2 N KOH). Later acidic treatment (concen-
trated HCl) yielded the corresponding anti 3-arylglutamic
acid hydrochlorides 15. These anti open-chain amino
acids were always isolated together with minor and
variable amounts of the corresponding cyclic pyroglutam-
ic acid derivative 21. From these mixtures the corre-
sponding pyroglutamic acid 21 can be ring opened by
refluxing with 1 N HCl to give hydrochloride 15. In the
case of 15d it was found that the minor cyclic product
21d from a 60:40 mixture of 15d /21d was completely
a
Conditions: (i) THF, -78 °C; (ii) 50% HBF4, THF, -78 to +20
converted into the major acyclic derivative 15d , when a
°C; (iii) 50% HBF4, THF, 0 to 20 °C; (iv) Et3N, 0 to 20 °C.
solution in MeOD (NMR sample) was allowed to stand
at room temperature for 3 d. The anti relative configu-
ration of hydrochloride 15d was confirmed by cyclization
of this amino acid to the corresponding ethyl pyro-
glutamate 12d (J H2,H3 ) 5.7 Hz, which indicates a trans
relationship between the substituents) with thionyl
chloride in ethanol. The free amino acid can be isolated
from the corresponding hydrochloride by reaction with
propylene oxide or by cation-exchange chromatography
(Dowex resin); in the case of 15a a mixture of (2R,3S)-
3-phenylglutamic acid (17a ) and its cyclized product
(2R,3S)-3-phenylpyroglutamic acid (21a ) was obtained.
Cyclic Am in oca r ben e Com p lexes. Syn th esis of
3-Su bstitu ted P yr oglu ta m ic Acid s. We found that
deprotection of the benzophenone imine of anti Michael
adducts 4 transformed these open-chain alkoxycarbene
complexes to the corresponding cyclic aminocarbene
derivatives 22 and 23 (Scheme 6). Consequently, succes-
sive treatment of 4 with 50% aqueous solution of HBF4
and then with Et3N led to an easily separable (silica gel
column chromatography) mixture of diastereoisomeric
aminocarbene complexes 22 (J H2,H3 ) 4-6 Hz) and 23
(J H2,H3 ) 6-10 Hz) in which the trans isomer 22 was
always the major product (Table 3, entries 1-3). This
procedure represents a milder and more direct way to
remove the chiral auxiliary group. A 2 N solution of HCl
Ta ble 3. Dia ster eoselective Syn th esis of Cyclic
Am in oca r ben e Com p lexes of Ch r om iu m 22
starting glycine
entry complex anion
yield 22:23
R2 producta (%)b ratioc
R1
Ph
1
2
3
4
5
6
7
4bd
4cd
4h d
1a
1b
1e
t-Bu rac-22b
40e 68:32
2-furyl Et
2-furyl Et
rac-22c
22c
56
53
56
62
95
66
68:32
74:26
80:20
73:27
94:6
2a
2a
2a
2a
Ph
2-furyl Et
Ph Et
2-furyl Et
Et
rac-22a
rac-22c
22a f
1f
22cg
92:8
a
b
Only the major diastereoisomer is shown. Isolated yield
based on the corresponding carbene complex 1 or 4. c Diastereo-
meric ratio determined by 1H NMR spectroscopy; integration of
d
the CH-N signal. Used as the mixture of anti/syn diastereoiso-
mers shown in Table 1. e Using 2 N HCl instead of 50% HBF4
aqueous solution, the reaction took a longer time (21 h vs 6 h)
and a 78:22 mixture of rac-22b/rac-23b was formed in 43% yield.
f 87% ee, determined by HPLC analysis on a chiral support. g 78%
ee, determined by HPLC analysis on a chiral support.
can be alternatively used instead of 50% HBF4 in H2O,
although in the former case the hydrolysis reaction was
slower (Table 3, entry 1). Furthermore, these cyclic
aminocarbene complexes can be directly and more ef-
ficiently synthesized from the reaction of alkenylcarbene
complexes 1 with glycine anion 2 as shown in Scheme 6

6560 J . Org. Chem., Vol. 64, No. 18, 1999
Ezquerra et al.
Sch em e 7a
and hydrolysis of the initial 1,4-adducts. Cyclic ami-
nocarbene complexes 22, which in addition are stable
compounds, may be envisaged as valuable intermediates
for the asymmetric synthesis of more highly substituted
glutamic acid derivatives.
Exp er im en ta l Section
Gen er a l P r oced u r es. TLC was carried out on glass-backed
silica gel plates coated with F254; the chromatograms were
visualized under ultraviolet light or by staining with Ce/Mo
solution or with ninhydrin solution and subsequent heating.
Flash column chromatography was performed on silica gel 60,
230-240 mesh. Ion-exchange chromatography was performed
on Dowex 50wx8-100. Optical rotations were measured at room
temperature, and concentration is reported in g/100 mL.
Carbon multiplicities were assigned according to the outcome
of DEPT experiments. Enantiomeric excess was determined
by HPLC analysis (in comparison with the corresponding
racemic mixtures) carried out on a Chiralcel OD-H chiral
column with a UV/vis photodiode array detector and employing
mixtures of hexane/i-PrOH of ratio 8:1 for 22a and 75:1 for
22c as eluants, flow rate 1.0 mL/min.
a
Key: (i) C5H5N+-O-, THF, rt; (ii) 2.5 N LiOH, THF, rt, then
HCl. b Yield based on recovered starting carbene complex was 46%.
Sch em e 8a
Et2O and THF were freshly dried by distillation from sodium
benzophenone under nitrogen. CH2Cl2 and MeOH were dis-
tilled from CaH2 and stored over 4 Å molecular sieves. Hexane
was distilled over P2O5. The following chemicals were prepared
according to literature procedures: pentacarbonyl[1-[(1R*,-
2S*,5R*)-menthyloxy]ethylidene]chromium,30 pentacarbonyl-
[1-[(1R,2S,5R)-8-phenylmenthyloxy]ethylidene]chromium,23b
pentacarbonyl[(E)-3-phenyl-1-[(1R,2S,5R)-8-phenylmenthyloxy]-
2-propenylidene]chromium (1e),23b pentacarbonyl[(E)-3-(2-fur-
yl)-1-[(1R,2S,5R)-8-phenylmenthyloxy]-2-propenylidene]chro-
mium (1f),23b ethyl N-(diphenylmethylidene)glycinate,31 tert-
butyl N-(diphenylmethylidene)glycinate,31 ethyl N,N-dibenzyl-
glycinate,32 tert-butyl N,N-dibenzylglycinate,32 1-(ethoxycar-
bonylmethyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilolidine,33 and
trans-1-iodo-1-hexene.34 All the other chemicals were com-
mercially available and were used as received. Carbene
complexes 1a , 1b, 1e, and 1f were easily handled by storing
them in THF solution at -20 °C under a nitrogen atmosphere.
Experimental procedures and spectral data for compounds
not described here are presented in the Supporting Informa-
tion.
Gen er a l P r oced u r e for th e Syn th esis of Ca r ben e
Com p lexes 4 a n d 5. All the operations were carried out under
a nitrogen atmosphere. LDA (1.6 equiv) was prepared by
adding 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, the
LDA solution was cooled to -78 °C, and a solution of the
appropriate protected glycine ester (1.6 equiv) was added via
an addition funnel. The resulting yellow-orange solution of 2
or 3 was stirred for 30 min at -78 °C, and then, a THF solution
of the corresponding alkenylcarbene complex 1 (1 equiv) was
added dropwise from the addition funnel at -78 °C. Once the
addition was concluded, the dark red starting carbene solution
turned into a bright yellow one. After being stirred for 1-3 h
at -78 °C, the reaction mixture was quenched with silica gel
and allowed to quickly warm to room temperature by removing
the cold bath. THF was removed under reduced pressure, and
the silica-adsorbed product was placed on the top of a column
and purified by flash chromatography. Elution with hexane/
CH2Cl2, 9:1, removed some remaining starting carbene com-
plex and no polar materials. Sequential elution with hexane/
CH2Cl2, 4:1 and 1:1, gave pure carbene complexes 4 or 5 as
one major diastereoisomer in the chiral examples (4f-i, 5m ,n )
a
Reagents: (i) MeI, Cs2CO3, Me2CO, H2O, rt; (ii) C5H5N+-O-,
THF, rt; (iii) CH3COCl, MeOH, rt.
and Table 3, entries 4-7. This one-pot process afforded
the trans isomer 22 with good diastereoselectivity, which
was particularly high, and better than in the two-step
reaction, when the chiral (-)-8-phenylmenthyloxy de-
rivatives 1e,f were employed (Table 3, entry 7 vs 3).
Compounds 22a and 22c were also formed with high
enantiomeric purity (87% and 78% ee, respectively; Table
3, entries 6 and 7), although this level of facial selectivity
is somewhat lower that the previously observed in the
Michael addition of ketone lithium enolates to chiral
carbene complexes 1e,f.23b Aminocarbene complexes 22
were transformed to the corresponding racemic or opti-
cally active lactams 12 by oxidative removal of the metal
fragment with pyridine N-oxide (Scheme 7). This oxida-
tion was also a very slow reaction, providing the ethyl
pyroglutamate substrates 12 with moderate chemical
yields. Experiments carried out using other solvents such
as MeOH or ethyl acetate or other oxidants such as PhIO
led to worse results. Basic hydrolysis of esters 12 with
2.5 N LiOH followed by acidic treatment yielded the
enantiomerically enriched 3-arylpyroglutamic acids 21a,c.
The structure of these cyclic products was confirmed by
conversion of two of them to known cyclic lactam deriva-
tives as detailed in Scheme 8. Aminocarbene complex rac-
22a was methylated on the nitrogen in the presence of
Cs2CO3 as a base29 to give complex rac-24 which was
subsequently transformed into rac-2528b by oxidation of
the chromium-carbon double bond. Likewise, trans-
esterification of 12a furnished 26.2a
In conclusion, our results demonstrate that the dia-
stereoselective conjugate addition of achiral glycine syn-
thons to chiral alkenylcarbene complexes represents a
novel synthetic approach to racemic and optically en-
riched â-substituted glutamic or pyroglutamic acids,
which are formed after sequential deprotection, oxidation,
(30) So¨derberg, B. C.; Hegedus, L. S.; Sierra, M. A. J . Am. Chem.
Soc. 1990, 112, 4364.
(31) O’Donnell, M. J .; Polt, R. L. J . Org. Chem. 1982, 47, 2663.
(32) Banfi, L.; Cardani, S.; Potenza, D.; Scolastico, C. Tetrahedron
1987, 43, 2317.
(33) Djuric, S.; Venit, J .; Magnus, P. Tetrahedron Lett. 1981, 22,
1787.
(34) Stille, J . K.; Simpson, J . H. J . Am. Chem. Soc. 1987, 109, 2138.
(29) Sabate´, R.; Schick, U.; Moreto´, J . M.; Ricart, S. Organometallics
1996, 15, 3611.

Synthesis of â-Substituted Glutamic Acids
J . Org. Chem., Vol. 64, No. 18, 1999 6561
and as an aproximately 1:1 mixture of two major diastereoi-
somers in the racemic examples (4a -e, 5j-l).
(0.89 mmol, 89% yield) of 4i as a yellow solid in 97:3 ds: mp
128-129 °C; Rf ) 0.31 (hexane/CH2Cl2, 1:1). Data taken from
a pure sample of 4i: [R]D ) +68.4 (c 0.5, CHCl3); IR (film) ν
P en t a ca r b on yl[(3S,4R)-4-[N-(d ip h en ylm et h ylid en e)-
a m in o]-4-eth oxyca r bon yl-3-p h en yl-1-[(1R,2S,5R)-8-p h en -
ylm en th yloxy]bu tyliden e]ch r om iu m (4f). Ethyl N-(diphen-
ylmethylidene)glycinate (0.91 g, 3.4 mmol) in THF (15 mL)
was treated with LDA prepared from i-Pr2NH (0.45 mL, 3.4
mmol) and BuLi (2.5 M in hexane, 3.4 mmol) in THF (8 mL),
according to the general procedure. After 30 min at -78 °C, a
0.425 M THF solution of carbene complex 1e (5 mL, 2.125
mmol) was diluted in THF (20 mL) and added to the glycinate
anionic solution of 2a at -78 °C. The reaction mixture was
stirred for 2 h at -78 °C and worked up as described above.
Flash chromatography of the crude product afforded 1.10 g
(1.3 mmol, 65% yield) of 4f as a yellow foam in 96:4 ds: Rf )
0.45 (hexane/CH2Cl2, 1:1). Data on the 96:4 diastereomeric
mixture: [R]D ) +82.2 (c 0.65, CHCl3); IR (film) ν (cm-1) 2063,
1950, 1741; 1H NMR (CDCl3, 300 MHz) δ 7.84-7.61 (4 H, m),
7.58-7.13 (14 H, m), 6.85 (2 H, m), 4.98 (1 H, td, J ) 10.3, 3.9
Hz), 3.97 (5 H, m), 2.29 (1 H, t, J ) 11.6 Hz), 2.09 (1 H, m),
1.63 (2 H, m), 1.35 (1 H, m), 1.27-1.03 (11 H, m + 2s + t, J )
1
(cm-1) 2058, 1934, 1738, 1624; H NMR (CDCl3, 300 MHz) δ
7.72 (2 H, d, J ) 6.9 Hz), 7.50-7.15 (13 H, m), 6.93 (2 H, m),
5.99 (1 H, d, J ) 1.5 Hz), 5.10 (1 H, td, J ) 10.7, 4.1 Hz),
4.11-3.99 (2 H, m), 3.93 (1 H, d, J ) 6.0 Hz), 3.92-3.84 (1 H,
m), 3.78 (1 H, dd, J ) 11.4, 3.1 Hz), 2.27 (1 H, m), 2.11 (1 H,
t, J ) 11.3 Hz), 1.82 (1 H, m), 1.52 (2 H, m), 1.50 (1 H, m),
1.25 (7 H, d + m, J ) 1.2 Hz), 1.23-1.13 (4 H, t + m, J ) 7.1
Hz), 0.87-0.78 (4 H, d + m, J ) 6.4 Hz); 13C NMR (CDCl3, 75
MHz) δ 356.5 (C), 222.6 (C), 216.3 (C), 171.3 (C), 170.2 (C),
151.0 (C), 141.6 (CH), 140.1 (CH), 139.0 (C), 135.8 (C), 132.3
(CH), 130.5 (CH), 129.9 (CH), 128.9 (CH), 128.4 (CH), 128.3
(CH), 128.1 (CH), 127.9 (CH), 125.4 (CH), 125.3 (CH), 123.3
(C), 111.0 (CH), 92.7 (CH), 70.6 (CH), 63.8 (CH2), 60.8 (CH2),
50.9 (CH), 41.3 (CH2), 39.5 (C), 37.8 (CH), 33.9 (CH2), 30.6
(CH), 27.8 (CH), 26.1 (CH2), 24.1 (CH3), 21.5 (CH3), 13.8 (CH3);
MS m/z 711 (M+ - 3CO, 2.6), 655 (M+ - 5CO, 67), 530 (32),
274 (63), 119 (100). Anal. Calcd for C45H45CrNO9: C, 67.91;
H, 5.69; N, 1.75. Found: C, 67.85; H, 5.63; N, 1.73.
7.3 Hz), 0.86 (1 H, m), 0.73-0.60 (4 H, m + d, J ) 6.4 Hz); 13
C
P en tacar bon yl[(3S,4S)-4-(N,N-diben zylam in o)-4-eth oxy-
ca r b on yl-3-p h en yl-1-[(1R,2S,5R)-8-p h en ylm en t h yloxy]-
bu tylid en e]ch r om iu m (5m ). Ethyl N,N-dibenzylglycinate
(0.68 g, 2.4 mmol) in THF (12 mL) was treated with LDA
prepared from i-Pr2NH (0.31 mL, 2.4 mmol) and BuLi (2.5 M
in hexane, 2.4 mmol) in THF (7 mL), according to the general
procedure. After 30 min at -78 °C, a 0.33 M THF solution of
carbene complex 1e (4.5 mL, 1.5 mmol) was diluted in THF
(12 mL) and added to the glycinate anionic solution of 3a at
-78 °C. The reaction mixture was stirred for 3 h at -78 °C
and worked up as described above. Flash chromatography of
the crude product afforded 1.06 g (1.28 mmol, 86% yield) of
5m as a yellow foam in 90:10 ds: Rf ) 0.53 (hexane/CH2Cl2,
1:1). Data taken from the 90:10 diastereomeric mixture:
[R]D ) +75.3 (c 1.21, CHCl3); IR (film) ν (cm-1) 2058, 1940,
1728, 1454; 1H NMR (CDCl3, 300 MHz) δ 7.46-7.02 (15 H,
m), 6.91-6.79 (4 H, m), 6.53 (1 H, d, J ) 7.3 Hz), 4.76 (1 H,
td, J ) 10.8, 4.3 Hz), 4.46-4.31 (2 H, m), 3.75 (4 H, d + m,
J ) 14.1 Hz), 3.24 (3 H, m + d, J ) 13.8 Hz), 3.03 (1 H, d,
J ) 11.2 Hz), 2.02 (1 H, td, J ) 9.9, 3.0 Hz), 1.87 (1 H, d, J )
3.0 Hz), 1.59 (1 H, m), 1.49 (3 H, t, J ) 7.3 Hz), 1.43-1.06 (8
H, m), 1.02 (1 H, m), 0.87 (1 H, t, J ) 6.9 Hz), 0.68 (4 H, d +
m, J ) 6.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 355.0 (C), 222.5
(C), 216.2 (C), 170.4 (C), 151.4 (C), 138.6 (C), 138.4 (C), 129.7
(CH), 129.2 (CH), 128.9 (CH), 127.9 (CH), 127.7 (CH), 127.5
(CH), 126.8 (CH), 126.5 (CH), 125.2 (CH), 91.5 (CH), 65.8
(CH2), 65.4 (CH), 60.4 (CH2), 54.1 (CH2), 50.4 (CH), 43.4 (CH),
40.4 (CH2), 39.0 (C), 34.0 (CH2), 30.5 (CH), 29.8 (CH3), 25.6
(CH2), 22.1 (CH3), 21.4 (CH3), 14.7 (CH3).
NMR (CDCl3, 75 MHz) δ 356.6 (C), 222.7 (C), 216.4 (C), 171.7
(C), 170.2 (C), 151.0 (C), 139.4 (C), 139.0 (C), 135.9 (C), 132.3
(CH), 130.5 (CH), 130.0 (CH), 129.5 (CH), 129.0 (CH), 128.4
(CH), 128.2 (CH), 127.9 (CH), 127.7 (CH), 127.5 (CH), 126.8
(CH), 125.5 (CH), 125.3 (CH), 92.5 (CH), 71.2 (CH), 63.9 (CH2),
60.8 (CH2), 50.6 (CH), 47.1 (CH), 41.4 (CH2), 39.4 (C), 33.8
(CH2), 30.5 (CH), 27.7 (CH3), 26.0 (CH2), 24.5 (CH3), 21.4 (CH3),
13.8 (CH3).
P en t a ca r b on yl[(3R,4R)-4-[N-(d ip h en ylm et h ylid en e)-
am in o]-4-eth oxycar bon yl-3-(2-fu r yl)-1-[(1R,2S,5R)-8-ph en -
ylm en th yloxy]bu tylid en e]ch r om iu m (4h ). Ethyl N-(di-
phenylmethylidene)glycinate (0.43 g, 1.6 mmol) in THF (10
mL) was treated with LDA prepared from i-Pr2NH (0.21 mL,
1.6 mmol) and BuLi (2.5 M in hexane, 1.6 mmol) in THF (5
mL), according to the general procedure. After 30 min at -78
°C, a 0.33 M THF solution of carbene complex 1f (3 mL, 1
mmol) was diluted in THF (10 mL) and added to the glycinate
anionic solution of 2a at -78 °C. The reaction mixture was
stirred for 1 h at -78 °C and worked up as described above.
Flash chromatography of the crude product afforded 0.55 g
(0.69 mmol, 69% yield) of 4h as a yellow solid in 91:9 ds: mp
103-104 °C; Rf ) 0.31 (hexane/CH2Cl2, 1:1). Data taken from
a pure sample of 4h : [R]D ) +86.6 (c 0.5, CHCl3); IR (film) ν
1
(cm-1) 2058, 1936, 1738, 1624; H NMR (CDCl3, 200 MHz) δ
7.70 (2 H, d, J ) 6.7 Hz), 7.45-7.12 (11 H, m), 7.14 (1 H, m),
6.94 (2 H, m), 6.23 (1 H, t, J ) 1.9 Hz), 5.94 (1 H, d, J ) 3.1
Hz), 5.22 (1 H, td, J ) 10.6, 4.2 Hz), 4.13 (1 H, d, J ) 5.8 Hz),
4.08-3.94 (4 H, m), 2.95 (1 H, dd, J ) 14.3, 11.3 Hz), 2.20 (1
H, td, J ) 12.5, 3.4 Hz), 1.83 (1 H, m), 1.53 (4 H, m), 1.28 (3
H, s), 1.23-1.13 (4 H, m + t, J ) 7.3 Hz), 1.06 (3 H, s), 0.89-
0.76 (4 H, m + d, J ) 6.1 Hz); 13C NMR (CDCl3, 75 MHz) δ
354.7 (C), 223.5 (C), 216.3 (C), 171.7 (C), 170.2 (C), 153.5 (C),
150.5 (C), 140.9 (CH), 139.1 (C), 135.9 (C), 132.3 (CH), 130.5
(CH), 130.0 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH), 128.2
(CH), 127.9 (CH), 127.5 (CH), 125.4 (CH), 125.3 (CH), 110.2
(CH), 107.5 (CH), 93.0 (CH), 63.2 (CH2), 60.9 (CH2), 50.9 (CH),
42.4 (CH2), 40.0 (CH), 39.9 (C), 33.9 (CH2), 30.7 (CH), 27.1
(CH3), 26.4 (CH2), 25.1 (CH3), 21.6 (CH3), 13.9 (CH3); MS m/z
711 (M+ - 3CO, 0.1), 655 (M+ - 5CO, 2.7), 337 (29), 123 (85),
119 (100). Anal. Calcd for C45H45CrNO9: C, 67.91; H, 5.69; N,
1.75. Found: C, 68.08; H, 5.66; N, 1.79.
Gen er a l P r oced u r e for Oxid a tion of Ca r ben e Com -
p lexes 4 a n d 5. Meth od s A a n d C. Carbene complexes 4 or
5 were placed in a round-bottom flask, flushed with N2, and
dissolved in THF (method A) or Et2O (method C). Pyridine
N-oxide (4-9 equiv) was added, and the reaction mixture was
allowed to stir for 2-4 d. 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 the oxidation was
concluded. 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 bulblight.
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 (9f-i, 6m ) and as a roughly 1:1 mixture of two major
diastereoisomers in the racemic examples (9a -c, 6j).
P en t a ca r b on yl[(3S,4R)-4-[N-(d ip h en ylm et h ylid en e)-
am in o]-4-eth oxycar bon yl-3-(3-fu r yl)-1-[(1R,2S,5R)-8-ph en -
ylm en th yloxy]bu tylid en e]ch r om iu m (4i). Ethyl N-(di-
phenylmethylidene)glycinate (0.43 g, 1.6 mmol) in THF (10
mL) was treated with LDA prepared from i-Pr2NH (0.21 mL,
1.6 mmol) and BuLi (2.5 M in hexane, 1.6 mmol) in THF (5
mL), according to the general procedure. After 30 min at -78
°C, a 0.33 M THF solution of carbene complex 1g (3 mL, 1
mmol) was diluted in THF (10 mL) and added to the glycinate
anionic solution of 2a at -78 °C. The reaction mixture was
stirred for 1 h at -78 °C and worked up as described above.
Flash chromatography of the crude product afforded 0.70 g
1-Eth yl 5-[(1R,2S,5R)-8-P h en ylm en th yl](2S,3S)-2-(N,N-
d iben zyla m in o)-3-p h en ylglu ta r a te (6m ). Meth od C. Car-

6562 J . Org. Chem., Vol. 64, No. 18, 1999
Ezquerra et al.
bene complex 5m (1 g, 1.2 mmol) was dissolved in Et2O (150
mL) and allowed to react with pyridine N-oxide (1 g, 10 mmol)
for 4 d. Then, solvents were evaporated, and the residue was
taken up in EtOAc (50 mL), treated as described above, and
air oxidized for 2 d. Flash chromatography of the crude product
(hexane/EtOAc, 9:1) yielded 0.46 g (0.71 mmol, 59% yield) of
6m as an oil in 95:5 ds: Rf ) 0.3 (hexane/EtOAc, 9:1). Data
taken from the 95:5 mixture: [R]D ) +25.5 (c 1.78, CHCl3);
9.2 Hz), 7.46-7.33 (8 H, m), 7.31-7.18 (4 H, m), 7.09-7.04 (1
H, m), 6.88 (2 H, m), 6.18 (1 H, dd, J ) 3.2, 1.8 Hz), 5.96 (1 H,
d, J ) 3.2 Hz), 4.80 (1 H, td, J ) 10.7, 4.3 Hz), 4.29 (1 H, d,
J ) 5.3 Hz), 4.16 (2 H, m), 3.99 (1 H, m), 2.45 (2 H, d, J ) 8.1
Hz), 2.0 (1 H, m), 1.65 (3 H, m), 1.40-1.25 (10 H, m + 2s + t,
J ) 6.9 Hz), 1.05 (1 H, m), 0.83 (5 H, m + d, J ) 6.5 Hz); 13C
NMR (CDCl3, 75 MHz) δ 171.4 (C), 171.3 (C), 170.3 (C), 153.9
(C), 151.3 (C), 141.0 (CH), 139.2 (C), 135.8 (C), 129.9 (CH),
128.8 (CH), 128.4 (CH), 128.1 (CH), 127.8 (CH), 127.7 (CH),
127.5 (CH), 125.2 (CH), 124.9 (CH), 109.9 (CH), 106.5 (CH),
74.2 (CH), 67.6 (CH), 60.9 (CH2), 50.2 (CH), 41.4 (CH2), 39.5
(C), 38.9 (CH), 34.3 (CH2), 34.0 (CH2), 31.0 (CH), 27.1 (CH3),
26.4 (CH2), 25.3 (CH3), 21.6 (CH3), 14.0 (CH3); MS m/z 619
(M+, 4.5), 266 (100), 193 (35.7); HRMS calcd for C40H45NO5
619.3297, found 619.3288.
1
IR (film) ν (cm-1) 1728; H NMR (CDCl3, 300 MHz) δ 7.49-
7.05 (14 H, m), 6.85 (6 H, m), 4.58 (1 H, td, J ) 10.7, 4.4 Hz),
4.49-4.32 (2 H, m), 3.89 (2 H, d, J ) 13.6 Hz), 3.66 (1 H, td,
J ) 11.1, 4.2 Hz), 3.45 (1 H, d, J ) 11.6 Hz), 3.27 (2 H, d, J )
13.7 Hz), 2.00 (1 H, dd, J ) 14.4, 4.1 Hz), 1.78 (2 H, dd + m,
J ) 14.4, 10.8 Hz), 1.53 (5 H, t + m, J ) 7.0 Hz), 1.27 (7 H,
2s + m), 1.04 (3 H, m), 0.76 (4 H, d + m, J ) 6.4 Hz); 13C
NMR (CDCl3, 75 MHz) δ 170.5 (C), 170.4 (C), 151.1 (C), 139.4
(C), 138.5 (C), 128.9 (CH), 128.8 (CH), 127.7 (CH), 127.6 (CH),
127.5 (CH), 126.6 (CH), 126.4 (CH), 125.1 (CH), 124.7 (CH),
73.6 (CH), 64.3 (CH), 60.0 (CH2), 53.9 (CH2), 49.8 (CH), 41.5
(CH), 40.7 (CH2), 39.3 (C), 39.0 (CH2), 34.1 (CH2), 30.7 (CH),
27.2 (CH3), 26.1 (CH2), 24.9 (CH3), 21.3 (CH3), 14.6 (CH3); MS
m/z 572 (M+ - CO2Et, 2.7), 358 (3.3), 282 (100); HRMS calcd
for C43H51NO4 645.3818, found 645.3812.
1-Eth yl 5-[(1R,2S,5R)-8-P h en ylm en th yl](2R,3S)-2-[N-
(d ip h en ylm et h ylid en e)a m in o]-3-p h en ylglu t a r a t e (9f).
Meth od C. Carbene complex 4f (1.40 g, 1.75 mmol) was
dissolved in Et2O (50 mL) and treated with pyridine N-oxide
(1.48 g, 15.6 mmol) for 60 h. The suspension was filtered
through Celite, more pyridine N-oxide (1.31 g, 13.84 mmol)
was added, and the reaction was stirred at room temperature
for 30 h. Then, solvents were evaporated, and the residue was
taken up in EtOAc (50 mL), treated as described above, and
air oxidized for 48 h. Flash chromatography of the crude
product (hexane/EtOAc, 9:1) yielded 0.70 g (1.10 mmol, 64%
yield) of 9f as a white solid in 87:13 ds.
1-Eth yl 5-[(1R,2S,5R)-8-P h en ylm en th yl](2R,3S)-2-[N-
(d ip h en ylm eth ylid en e)a m in o]-3-(3-fu r yl)glu ta r a te (9i).
Meth od A. Carbene complex 4i (1.12 g, 1.40 mmol) was
dissolved in THF (40 mL) and treated with pyridine N-oxide
(0.53 g, 5.63 mmol) for 3 d. Then, the reaction mixture was
filtered through Celite and treated again with pyridine N-oxide
(0.53 g, 5.63 mmol) for 4 d. Solvents were evaporated, and the
residue was taken up in EtOAc (100 mL), treated as described
above, and air oxidized for 24 h. Flash chromatography of the
crude product (hexane/EtOAc, 9:1) yielded 0.44 g (0.70 mmol,
52% yield) of 9i as a white foam in 100:0 ds: Rf ) 0.48 (hexane/
EtOAc, 9:1); [R]D ) +100.0 (c 2.6, CHCl3); IR (film) ν 1728,
1
1626; H NMR (CDCl3, 300 MHz) δ 7.76 (2 H, d, J ) 7.9 Hz),
7.50-7.41 (6 H, m), 7.33-7.28 (5 H, m), 7.20 (1 H, s), 7.12 (1
H, m), 7.00 (1 H, m), 6.16 (1 H, m), 4.82 (1 H, td, J ) 10.6, 4.0
Hz), 4.23-4.14 (3 H, m + d, J ) 5.7 Hz), 3.88 (1 H, m), 2.43 (1
H, dd, J ) 15.4, 4.0 Hz), 2.28 (1 H, dd, J ) 15.4, 11.3 Hz),
2.02 (1 H, m), 1.76-1.59 (3 H, m), 1.44-1.32 (4 H, s + m),
1.27 (6 H, t + s, J ) 7.4 Hz), 1.15 (1 H, m), 0.94-0.80 (5 H,
m + d, J ) 6.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 171.4 (C),
171.0 (C), 170.3 (C), 151.3 (C), 142.0 (CH), 139.6 (CH), 139.0
(C), 135.7 (C), 130.3 (CH), 128.7 (CH), 128.3 (CH), 128.1 (CH),
127.8 (CH), 127.6 (CH), 127.4 (CH), 125.1 (CH), 124.8 (CH),
124.1 (C), 110.1 (CH), 73.9 (CH), 69.3 (CH), 60.6 (CH2), 50.0
(CH), 41.1 (CH2), 39.3 (C), 36.1 (CH), 35.8 (CH2), 34.2 (CH2),
30.9 (CH), 27.6 (CH3), 26.2 (CH2), 24.6 (CH3), 21.5 (CH3), 13.0
(CH3); MS m/z 619 (M+, 33), 546 (M+ - CO2Et, 2), 404 (12)
266 (100); HRMS calcd for C40H45NO5 619.3297, found 619.3286.
Anal. Calcd for C40H45NO5: C, 77.51; H, 7.31; N, 2.26. Found:
C, 76.83; H, 7.45; N, 2.13.
Meth od A. Carbene complex 4f (1.57 g, 1.94 mmol) was
dissolved in THF (70 mL) and allowed to react with pyridine
N-oxide (1.61 g, 17 mmol) for 4 d. The suspension was filtered
through Celite, more pyridine N-oxide (1.47 g, 15 mmol) was
added, and the reaction was stirred at room temperature for
30 h. Then, solvents were evaporated, and the residue was
taken up in EtOAc (50 mL), treated as described above, and
air oxidized for 30 h. Flash chromatography of the crude
product (hexane/EtOAc, 9:1) yielded 0.86 g (1.37 mmol, 71%
yield) of 9f as a white solid in 92:8 ds: mp 58-59 °C; Rf )
0.17 (hexane/EtOAc, 9:1). Data on the 92:8 mixture: [R]D
)
Gen er a l P r oced u r e for Ca ta lytic Hyd r ogen a tion of
Com p ou n d s 6. A hydrogenation bottle was sealed with a
rubber septum, evacuated, and filled with N2. In the bottle
were placed diester 6, 5% Pd/C (40% weight), and EtOH. The
bottle was set in the hydrogenator and charged with H2 (three
cycles to 40 psi). The reaction mixture was shaken at 50 °C
for 15 h; H2 was released, and the mixture was filtered through
a bed of Celite. The filtrate was concentrated under reduced
pressure to give the free amines. The crude products were quite
clean and could be used in the next step without purification;
however, for characterization purposes the compounds were
chromatographied on silica.
+127.9 (c 0.68, CHCl3); IR (film) ν (cm-1) 1728, 1624; 1H NMR
(CDCl3, 400 MHz) δ 7.72 (2 H, d, J ) 7.6 Hz), 7.50-7.34 (6 H,
m), 7.30 (4 H, m), 7.22 (3 H, m), 7.08 (3 H, m), 6.78 (2 H, d,
J ) 7.6 Hz), 4.71 (1 H, td, J ) 10.8, 4.3 Hz), 4.17 (1 H, d, J )
6.0 Hz), 4.11 (2 H, dq, J ) 7.2, 2.3 Hz), 3.93 (1 H, m), 2.51 (2
H, dd, J ) 15.4, 4.4 Hz), 2.43 (2 H, dd, J ) 15.4, 11.4 Hz),
1.94 (1 H, td, J ) 12.2, 3.2 Hz), 1.62 (2 H, m), 1.32 (5 H, m +
s), 1.22 (3 H, s), 1.18 (3 H, t, J ) 7.2 Hz), 1.05 (1 H, m), 0.94
(1 H, m), 0.82 (1 H, m), 0.76 (3 H, d, J ) 7.6 Hz); 13C NMR
(CDCl3, 75 MHz) δ 171.3 (C), 170.9 (C), 170.2 (C), 151.2 (C),
140.0 (C), 138.9 (C), 135.7 (C), 130.2 (CH), 128.6 (CH), 128.3
(CH), 128.1 (CH), 127.9 (CH), 127.7 (CH), 127.5 (CH), 127.2
(CH), 125.1 (CH), 124.7 (CH), 73.6 (CH), 69.9 (CH), 60.5 (CH2),
50.0 (CH), 45.2 (CH), 40.9 (CH2), 39.3 (C), 35.5 (CH2), 34.1
(CH2), 30.7 (CH), 27.5 (CH3), 26.1 (CH2), 24.5 (CH3), 21.3 (CH3),
13.7 (CH3).
Following this procedure hydrogenation of compound 6j
(0.40 g, 0.70 mmol) with 5% Pd/C (0.16 g) in EtOH (38 mL)
gave 0.25 g (0.65 mmol, 95%) of the previously described
primary amine 10a as a white solid.
1-Eth yl 5-[(1R,2S,5R)-8-P h en ylm en th yl](2S,3S)-2-am in o-
3-p h en ylglu ta r a te (10f). Hydrogenation of compound 6m
(0.42 g, 0.65 mmol) with 5% Pd/C (0.18 g) in EtOH (38 mL) as
described above gave 0.29 g (0.63 mmol, 99%) of 10f as an oil
in 95:5 ds. The product was characterized after flash chroma-
tography (hexane/EtOAc, 1:1): Rf ) 0.60 (hexane/EtOAc, 1:1).
Data on the 95:5 mixture: [R]D ) +4.2 (c 0.71, CHCl3); IR (film)
ν (cm-1) 3393, 3331, 1728; 1H NMR (CDCl3, 300 MHz) δ 7.29-
7.20 (8 H, m), 7.12-7.00 (2 H, m), 4.71 (1 H, td, J ) 10.8, 4.3
Hz), 4.14 (2 H, q, J ) 7.3 Hz), 3.59 (1 H, d, J ) 4.7 Hz), 3.44
(1 H, m), 2.36 (1 H, dd, J ) 15.5, 6.9 Hz), 2.24 (1 H, dd, J )
15.5, 8.2 Hz), 1.92 (1 H, m), 1.60 (1 H, m), 1.46-1.19 (14 H,
m + 2s), 1.05 (1 H, m), 0.88-0.68 (5 H, m + d, J ) 6.5 Hz);
1-E t h yl 5-[(1R,2S,5R)-8-P h en ylm en t h yl](2R,3R)-2-[N-
(d ip h en ylm eth ylid en e)a m in o]-3-(2-fu r yl)glu ta r a te (9h ).
Meth od A. Carbene complex 4h (0.44 g, 0.55 mmol) was
dissolved in THF/Et2O, 2:1 (30 mL), and treated with pyridine
N-oxide (0.47 g, 4.97 mmol) for 60 h at reflux. The reaction
was then allowed to cool to room temperature, solvents were
evaporated, and the residue was taken up in EtOAc (50 mL),
treated as described above, and air oxidized for 15 h. Flash
chromatography of the crude product (hexane/EtOAc, 9:1)
yielded 0.19 g (0.31 mmol, 56% yield) of 9h as an oil in 92:8
ds: Rf ) 0.30 (hexane/EtOAc/THF, 1:1:0.1). Data on the 92:8
diastereomeric mixture: [R]D ) +87.1 (c 1.0, CHCl3); IR (film)
ν (cm-1) 1730; 1H NMR (CDCl3, 300 MHz) δ 7.67 (2 H, d, J )

Synthesis of â-Substituted Glutamic Acids
J . Org. Chem., Vol. 64, No. 18, 1999 6563
13C NMR (CDCl3, 75 MHz) δ 174.2 (C), 171.3 (C), 151.4 (C),
138.3 (C), 128.3 (CH), 128.1 (CH), 127.7 (CH), 127.1 (CH),
125.3 (CH), 124.9 (CH), 74.1 (CH), 60.8 (CH2), 57.8 (CH), 50.1
(CH), 44.8 (CH), 41.2 (CH2), 39.5 (C), 36.8 (CH2), 34.3 (CH2),
31.0 (CH), 27.6 (CH3), 26.3 (CH2), 24.9 (CH3), 21.5 (CH3), 14.1
(CH3); MS m/z 465 (M+, 2), 392 (M+ - CO2Et, 5), 251 (10), 160
(69), 119 (100); HRMS calcd for C29H39NO4 465.2879, found
465.2881.
(c 0.50, 6 N HCl);36 1H NMR (D2O, 400 MHz) δ 7.25 (5 H, m),
4.45 (1 H, d, J ) 8.2 Hz), 3.88 (1 H, q, J ) 7.7 Hz), 2.76 (1 H,
dd, J ) 17.1, 8.7 Hz), 2.54 (1 H, dd, J ) 17.1, 6.3 Hz); 13C
NMR (D2O, 75 MHz) δ 181.5 (C), 177.1 (C) 140.2 (C), 129.0
(CH), 128.2 (CH), 127.9 (CH), 64.6 (CH), 43.0 (CH), 37.7 (CH2).
Gen er a l P r oced u r e for Hyd r olysis of Im in es 9. Syn -
th esis of Com p ou n d s 19 a n d 11i. To a solution of the
corresponding imine 9 in THF was added 5 N HCl (7-10
equiv), and the reaction mixture was stirred at room temper-
ature for 20-48 h. Solvents were evaporated under reduced
pressure until dryness to give a white solid containing the
crude product together with benzophenone. Purification of
hydrochlorides 19 was carried out by washing the solid with
hexane several times and drying it under vacuum. In the case
of compound 9i the corresponding hydrochloride turned out
to be difficult to precipitate, and it was found more convenient
to isolate the free amine 11i after the reaction medium was
basified.
1-Eth yl 5-[(1R,2S,5R)-8-P h en ylm en th yl](2R,3S)-2-am in o-
3-p h en ylglu ta r a te (11f).6c,35 To a solution of hydroxylamine
hydrochloride (27 mg, 0.38 mmol) in EtOH (15 mL) were added
sodium acetate (31 mg, 0.38 mmol) and compound 9f (0.24 g,
0.38 mmol). The mixture was refluxed for 3 h and then was
poured into water. Extraction with CH2Cl2 (twice) and column
chromatography of the concentrated extract on silica gel
(hexane/EtOAc, 1:1) yielded 0.13 g (0.28 mmol, 73% yield) of
11f as a white solid: mp 78-79 °C; Rf ) 0.48 (hexane/EtOAc,
1:1); [R]D ) -14.0 (c 0.75, CHCl3); IR (film) ν (cm-1) 3389, 3323,
1
1-Eth yl 5-[(1R,2S,5R)-8-P h en ylm en th yl](2R,3S)-2-am in o-
3-p h en ylglu ta r a te Hyd r och lor id e (19f). Compound 9f (0.45
g, 0.71 mmol) was allowed to react with 5 N HCl (1.4 mL, 7.0
mmol) in THF (12 mL) for 48 h. Workup of the reaction
followed by purification as described above afforded 0.33 g
(0.65 mmol, 92% yield) of compound 19f as a white solid: mp
212-213 °C dec; [R]D ) - 4.6 (c 0.50, MeOH); 1H NMR (DMSO-
d6, 300 MHz) δ 8.72 (3 H, br s), 7.32 (10 H, m), 4.57 (1 H, td,
J ) 10.7, 4.4 Hz), 4.31 (1 H, d, J ) 6.8 Hz), 4.09 (2 H, dq, J )
7.3, 2.9 Hz), 3.69 (1 H, m), 2.75 (1 H, dd, J ) 15.6, 4.5 Hz),
2.60 (1 H, dd, overlapped with DMSO signal), 1.91 (1 H, t,
J ) 9.7 Hz), 1.52 (2 H, br t), 1.10 (8 H, 2s + m), 1.04-0.92 (5
1728; H NMR (CDCl3, 300 MHz) δ 7.28-7.18 (8 H, m), 7.11
(2 H, m), 4.68 (1 H, td, J ) 10.8, 4.5 Hz), 3.97 (2 H, q, J ) 7.3
Hz), 3.49 (1 H, d, J ) 7.3 Hz), 3.25 (1 H, m), 2.42 (1 H, dd,
J ) 15.4, 5.6 Hz), 2.19 (1 H, dd, J ) 15.5, 9.5 Hz), 1.91 (1 H,
m), 1.58 (4 H, m), 1.39 (1 H, m), 1.30-1.23 (4 H, s + m), 1.18
(3 H, s), 1.05 (3 H, t, J ) 7.3 Hz), 0.99-0.73 (4 H, d + m, J )
6.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 174.1 (C), 171.3 (C), 151.2
(C), 139.7 (C), 128.1 (CH), 127.9 (CH), 127.6 (CH), 126.8 (CH),
125.1 (CH), 124.8 (CH), 74.0 (CH), 60.4 (CH2), 59.3 (CH), 50.0
(CH), 46.0 (CH), 40.9 (CH2), 39.4 (C), 36.3 (CH2), 34.1 (CH2),
30.8 (CH), 27.3 (CH3), 26.2 (CH2), 24.9 (CH3), 21.4 (CH3), 13.7
(CH3); MS m/z 465 (M+, 2), 392 (M+ - CO2Et, 3), 234 (18), 199
(16), 160 (55), 119 (100); HRMS calcd for C29H39NO4 465.2879,
found 465.2887. Anal. Calcd for C29H39NO4: C, 74.80; H, 8.44;
N, 3.00. Found: C, 73.97; H, 8.18; N, 3.08.
H, t + m, J ) 7.3 Hz), 0.85-0.75 (4 H, d + m, J ) 6.9 Hz); 13
C
NMR (DMSO-d6, 75 MHz) δ 169.8 (C). 167.9 (C), 150.4 (C),
136.2 (C), 128.5 (CH), 128.3 (CH), 127.8 (CH), 127.7 (CH),
125.3 (CH), 125.1 (CH), 73.9 (CH), 61.5 (CH2), 55.6 (CH), 49.5
(CH), 42.9 (CH), 40.5 (CH2), 36.6 (CH2), 33.7 (CH2), 30.4 (CH),
26.7 (CH3), 26.1 (CH2), 25.8 (CH3), 21.4 (CH3), 13.6 (CH3); MS
m/z 466.5 (M+ - HCl, 85), 252 (100), 119 (84), 105 (99). Anal.
Calcd for C29H40NO4Cl: C, 69.37; H, 8.03; N, 2.79. Found: C,
68.93; H, 7.84; N, 2.64.
Gen er a l P r oced u r e for Hyd r olysis of Com p ou n d s 10.
Syn th esis of Hyd r och lor id es 14. To a solution of amino
diesters 10 in MeOH was added a solution of 2 N KOH (5
equiv). The reaction mixture was stirred at reflux for 3-4 h.
Solvents were evaporated under reduced pressure, and the
residue was extracted with CH2Cl2. The aqueous residue was
acidified with 2 N HCl at 0 °C until pH 1-2 and extracted
again with CH2Cl2; the organic phases were combined, dried
over Na2SO4, and concentrated on a rotary evaporator to give
back the chiral auxiliary. The aqueous phase was evaporated
under reduced pressure until dryness to give a white solid
containing the crude product together with KCl. The solid was
washed with MeOH (twice); the solution was separated with
a pipet and concentrated in a rotary evaporator to afford a
yellow solid. This operation was repeated again, and finally
the crude hydrochloride was triturated with Et2O several times
and dried at 40 °C until a consistent solid was obtained.
1-Eth yl 5-[(1R,2S,5R)-8-P h en ylm en th yl](2R,3S)-2-am in o-
3-(3-fu r yl)glu ta r a te (11i). Imino diester 9i (0.57 g, 0.92
mmol) was treated with 5 N HCl (2 mL, 10 mmol) in THF (20
mL) for 36 h. Solvents were evaporated under reduced pres-
sure, and the residue was diluted with water and basified at
0 °C with saturated aqueous NaHCO3 solution until pH 8-9.
The mixture was extracted with EtOAc, washed with water
(twice) and brine, dried (Na2SO4), and concentrated under
reduced pressure to give the crude product. Purification by
column chromatography (hexane/EtOAc, 2:1, 1:1) afforded 0.31
g (0.68 mmol, 74% yield) of compound 11i as an oil and single
diastereoisomer: Rf ) 0.40 (hexane/EtOAc, 1:1); [R]D ) -12.5
(2S,3S)-3-P h en ylglu ta m ic Acid Hyd r och lor id e (14a ).
Amino diester 10f (0.26 g, 0.56 mmol) was treated with 2 N
KOH (1.4 mL, 2.79 mmol) according to the general procedure.
Workup of the reaction gave (-)-8-phenylmenthol (100 mg,
80% yield) and an aqueous residue which after purification
afforded 88 mg (0.34 mmol, 60% yield) of 14a as a yellow
solid: [R]D ) +83.0 (c 0.47, 1 N HCl); IR (KBr) ν (cm-1) 3385,
1
(c 1.46, CHCl3); IR (film) ν (cm-1) 3391, 3323, 1726, 1601; H
NMR (CDCl3, 200 MHz) δ 7.27-7.05 (7 H, m), 6.18 (1 H, s),
4.72 (1 H, td, J ) 10.8, 4.1 Hz), 4.07 (2 H, q, J ) 7.0 Hz), 3.44
(1 H, d, J ) 6.2 Hz), 3.19 (1 H, m), 2.24 (1 H, dd, J ) 15.6, 5.6
Hz), 2.01 (1 H, dd, J ) 15.6, 9.4 Hz), overlapped with 1.90 (1
H, m), 1.59 (4 H, m), 1.40-1.27 (4 H, m + s), 1.20-1.13 (6 H,
s + t, J ) 7.2 Hz), 1.03 (1 H, m), 0.86-0.68 (4 H, d + m, J )
6.5 Hz); 13C NMR (CDCl3, 50 MHz) δ 173.8 (C), 171.0 (C), 151.1
(C), 142.4 (CH), 139.4 (CH), 127.5 (CH), 125.0 (CH), 124.7
(CH), 123.4 (C), 109.5 (CH), 74.0 (CH), 60.4 (CH2), 58.0 (CH),
49.9 (CH), 40.9 (CH2), 39.2 (C), 36.6 (CH), 35.9 (CH2), 34.1
(CH2), 30.8 (CH), 27.4 (CH3), 26.1 (CH2), 24.6 (CH3), 21.4 (CH3),
13.7 (CH3). Anal. Calcd for C27H37NO5: C, 71.18; H, 8.18; N,
3.07. Found: C, 70.71; H, 8.54; N, 2.94.
1
3285, 1728, 1658; H NMR (MeOH-d4, 300 MHz) δ 7.47 (5 H,
m), 4.77 (1 H, d, J ) 8.2 Hz), 4.25 (1 H, q, J ) 8.3 Hz), 2.91 (2
H, d, J ) 8.3 Hz); 13C NMR (MeOH-d4, 50 MHz) δ 180.8 (C),
173.9 (C), 139.7 (C), 129.6 (CH), 129.1 (CH), 128.7 (CH), 63.0
(CH), 45.2 (CH), 37.4 (CH2); MS m/z 259 (M+, 15), 244 (22),
224 (M+ - Cl, 19), 206 (M+ - Cl - H2O, 57), 192 (21); HRMS
calcd for C11H14NO4 (M+ - Cl) 224.0923, found 224.0931.
(2S,3S)-3-P h en ylglu ta m ic Acid (16a ).8a Hydrochloride
14a (22 mg, 0.085 mmol) was dissolved in the minimum
amount of MeOH (1.5 mL); the same amount of propylene
oxide was added, and the reaction mixture was stirred at room
temperature for 30 min or until the product precipitated.
Solvents were evaporated under reduced pressure to give a
yellow solid. The operation was repeated. The resultant solid
was dried, triturated with Et2O several times, and dried again
at 40 °C until a consistent solid was obtained. 16a (16.0 mg,
0.075 mmol, 84% yield) was produced in this way: [R]D ) +180
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
15. Meth od A. To a solution of the corresponding hydrochlo-
ride 19b,g in CH2Cl2 was added trifluoroacetic acid, and the
(35) Compound 11f was also obtained by two alternative methods:
treatment of hydrochloride 19f with Et3N (2.5 equiv) in THF, 30 min,
25 °C, quantitative yield, and hydrogenation of compound 9f (5% Pd/
C, 30% weight) in EtOAc, 15 h, 25 °C, 65% yield.
(36) Lit.8a R (589 nm, 25 °C, l ) 1 dm, c ) 8.1 g dm-3 in 6 M HCl)
) +11.1.

6564 J . Org. Chem., Vol. 64, No. 18, 1999
Ezquerra et al.
reaction mixture was stirred at room temperature for 3 h.
Solvents were evaporated under reduced pressure until dry-
ness, and the residue was diluted with MeOH. Workup was
carried out following the same procedure described above for
hydrolysis of compounds 10.
Meth od B. The procedure used for hydrolysis of ethyl esters
19f and 11i was similar to that previously described for
compounds 10.
1:2) afforded 30 mg (0.13 mmol, 52% yield) of pyroglutamate
12d as an oil: Rf ) 0.37 (hexane/EtOAc, 1:2); [R]D ) +80.5 (c
1
0.58, CHCl3); IR (film) ν (cm-1) 1738, 1705; H NMR (CDCl3,
300 MHz) δ 7.45 (1 H, s), 7.42 (1 H, d, J ) 1.0 Hz), 6.43 (1 H,
d, J ) 1.0 Hz), 4.30 (2 H, q, J ) 7.0 Hz), 4.18 (1 H, d, J ) 5.7
Hz), 3.72 (1 H, m), 2.83 (1 H, dd, J ) 17.0, 9.2 Hz), 2.47 (1 H,
dd, J ) 17.0, 9.2 Hz), 1.33 (3 H, t, J ) 7.0 Hz); 13C NMR
(CDCl3, 50 MHz) δ 176.5 (C), 170.9 (C), 143.7 (CH), 138.9 (CH),
119.9 (C), 108.9 (CH), 62.0 (CH), 61.8 (CH2), 36.8 (CH2), 34.0
(CH), 14.0 (CH3).
(2R, 3S)-3-P h en ylglu ta m ic Acid Hyd r och lor id e (15a ).
Meth od A. Amino diester 19g (54 mg, 0.10 mmol) was treated
successively with trifluoroacetic acid (0.6 mL, 7 mmol) in CH2-
Cl2 (6 mL) and 2 N KOH (1.0 mL, 2.0 mmol) in MeOH (8 mL)
according to the general procedure. Workup of the reaction
gave (-)-8-phenylmenthol (21 mg, 88% yield) and an aqueous
residue which after purification afforded 19 mg (0.07 mmol,
73% yield) of 15a as a solid in 90:10 ds.
Meth od B. 19f (0.15 g, 0.29 mmol) was treated with 2 N
KOH (0.75 mL, 1.45 mmol) in MeOH (8 mL) according to the
general procedure. Workup of the reaction gave (-)-8-phenyl-
menthol (66 mg, 98% yield) and an aqueous residue which after
purification afforded 75 mg (0.28 mmol, 98% yield) of 15a as
a solid in 91:9 ds. Data on the 91:9 mixture: [R]D ) -33.9 (c
0.165, 6N HCl);37 IR (KBr) ν (cm-1) 3364, 1745, 1686; 1H NMR
(MeOH-d4, 300 MHz) δ 7.35 (5 H, m), 4.27 (1 H, d, J ) 4.8
Hz), 3.75 (1 H, m), 2.90 (1 H, dd, J ) 17.1, 9.2 Hz), 2.47 (1 H,
dd, J ) 17.1, 5.7 Hz); 13C NMR (MeOH-d4, 75 MHz) δ 179.8
(C), 173.8 (C), 143.7 (C), 130.2 (CH), 128.6 (CH), 128.0 (CH),
64.7 (CH), 45.5 (CH), 39.7 (CH2); MS m/z 259 (M+, 8), 241
(M+ - H2O, 9), 224 (M+ - Cl, 29), 206 (M+ - Cl - H2O, 100),
185 (87).
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
22 fr om Ca r ben e Com p lexes 1. All the operations were
carried out under a nitrogen atmosphere. LDA (1.6 equiv) was
prepared by adding 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, the LDA solution was cooled to -78 °C, and a
solution of the appropriate protected glycine ester (1.6 equiv)
was added via addition funnel. The resulting yellow-orange
solution was stirred for 30 min at -78 °C, and then, a THF
solution of the corresponding alkenylcarbene complex 1 (1
equiv) was added dropwise from the addition funnel at -78
°C. After the addition was concluded, the dark red starting
carbene solution turned into a bright yellow one. After the
solution was stirred for 1-3 h at -78 °C, 50% HBF4 aqueous
solution (10 equiv) was added dropwise, the cold bath was
removed, and the reaction mixture was stirred at room
temperature until TLC evidenced no opened additon product
(2 h). At that point, the reaction was cooled with an ice-
saltwater bath, and 12 equiv of Et3N was added via the
addition funnel. After 20 min the solution was poured into a
separatory funnel, EtOAc was added, and the organic phase
was collected, dried (Na2SO4), filtered through Celite, and
concentrated under reduced pressure to give a residue, whose
1H NMR analysis provided the diastereoselectivity of the
addition-cyclization reaction. Purification of the residue by
flash chromatography led to isolation of pure cyclic carbene
complexes 22.
P en ta ca r bon yl[(3R,4S)-3-eth oxyca r bon yl-4-p h en yl-2-
a za cyclop en tylid en e]ch r om iu m (22a ). Ethyl N-(diphenyl-
methylidene)glycinate (0.64 g, 2.4 mmol) in THF (15 mL) was
treated at -78 °C with LDA prepared from i-Pr2NH (0.31 mL,
2.4 mmol), BuLi (1.6 M in hexane, 2.4 mmol), and THF (5 mL).
After 30 min, a 0.33 M THF solution of carbene complex 1e
(4.5 mL, 1.5 mmol) was diluted in THF (15 mL) and added to
the glycinate anionic solution of 2a at -78 °C. The reaction
mixture was stirred for 3 h at low temperature, and then was
successively treated with 50% HBF4 (2.8 g, 16 mmol) and Et3N
(2.5 mL, 18 mmol) according to the general procedure. Workup
of the reaction as described above gave a crude material
containing carbene complex 22a in 94:6 ds. Flash chromatog-
raphy of the crude product (hexane/EtOAc, 6:1) afforded 0.58
g (1.4 mmol, 95% yield) of 22a as a yellow solid: mp 117-118
°C; Rf ) 0.31 (hexane/EtOAc, 6:1); [R]D ) +30.4 (c 0.5, CHCl3);
IR (film) ν (cm-1) 3289, 2054, 1923, 1728; 1H NMR (CDCl3,
300 MHz) δ 9.11 (1 H, br s), 7.40-7.26 (3 H, m), 7.16 (2 H, d,
J ) 6.9 Hz), 4.64 (1 H, d, J ) 5.6 Hz), 4.29 (2 H, m), 3.83 (1 H,
dd, J ) 18.9, 8.6 Hz), 3.64 (1 H, m), 3.45 (1 H, dd, J ) 18.9,
5.6 Hz), 1.30 (1 H, t, J ) 7.3 Hz); 13C NMR (CDCl3, 75 MHz)
δ 279.7 (C), 222.4 (C), 217.2 (C), 168.8 (C), 140.7 (C), 129.1
(CH), 127.6 (CH), 126.6 (CH), 75.1 (CH), 62.5 (CH2), 61.7 (CH2),
45.4 (CH), 13.9 (CH3); MS m/z 409 (M+, 2.5), 408 (M+ - 1, 8),
325 (M+ - 3CO, 3.5), 297 (M+ - 4CO, 3.5), 269 (M+ - 5CO,
100), 215 (26); HRMS calcd for C18H15CrNO7 409.0253, found
409.0256. Anal. Calcd for C18H15CrNO7: C, 52.80; H, 3.70; N,
3.42. Found: C, 52.35; H, 4.04; N, 3.37.
Hydrochloride 15a was converted into the free amino acid
by ion-exchange chromatography on Dowex H+ or by treatment
with propylene oxide in MeOH as described above for com-
pound 14a . In the first case, the resin was acidified with 1 N
HCl, charged into the column, and washed with 1 N HCl.
Hydrochloride 15a was dissolved in the minimun amount of
MeOH and applied to the column. The resin was eluted with
water until a neutral elution came out from the column and
then with 2 N NH4OH aqueous solution. The basic aliquots
were combined and concentrated under reduced pressure to
give a solid which was dried under vacuum, triturated with
1
Et2O, and dried again. H NMR analysis of the solid show a
nearly 1:1 mixture of glutamic 17a and pyroglutamic 21a acids
(75% yield). When 15a was treated with propylene oxide, a
solid 62:38 mixture of 17a /21a was obtained in 90% yield: 1H
NMR of this mixture (MeOH-d4, 300 MHz) δ 7.28 (m, 10 H,
17a + 21a ), 4.33 (d, 1 H, J ) 6.4 Hz, 17a ), 4.02 (d, 1 H, J )
6.4 Hz, 21a ), 3.65 (m, 1 H, 17a ), 3.45 (m, 1 H, 21a ), 2.75 (dd,
1 H, 17a overlapped with dd, 1 H, 21a ), 2.45 (dd, 1 H, 17a
overlapped with dd, 1 H, 21a ).
(2R,3S)-3-(3-F u r yl)glu ta m ic Acid Hyd r och lor id e (15d ).
Meth od B. 11i (0.26 g, 0.57 mmol) was treated with 2 N KOH
(1.5 mL, 2.85 mmol) in MeOH (10 mL) according to the general
procedure. Workup of the reaction gave (-)-8-phenylmenthol
(90 mg, 68% yield) and an aqueous residue which after
purification afforded 92 mg (0.36 mmol, 65% yield) of 15d as
a white solid: mp 120-121 °C; [R]D ) +236.8 (c 0.45, 1 N HCl);
1
IR (KBr) ν (cm-1) 3283, 1739, 1687, 1439; H NMR (MeOH-
d4, 200 MHz) δ 7.50 (2 H, d, J ) 1.2 Hz), 6.48 (1 H, t, J ) 1.2
Hz), 4.23 (1 H, d, J ) 5.4 Hz), 3.67 (1 H, m), 2.78 (1 H, dd,
J ) 16.8, 8.9 Hz), 2.41 (1 H, dd, J ) 16.8, 6.4 Hz); 13C NMR
(MeOH-d4, 75 MHz) δ 179.7 (C), 173.7 (C), 145.4 (CH), 140.7
(CH), 127.5 (C), 110.2 (CH), 64.0 (CH), 38.5 (CH2), 36.8 (CH).
Eth yl (2R,3S)-3-(3-F u r yl)p yr oglu ta m a te (12d ). A mix-
ture of amino acid 15d (66.5 mg, 0.26 mmol) and SOCl2 (75
µL, 1 mmol) was stirred at room temperature for 40 min. Then
absolute EtOH (3 mL) was added, and the mixture was allowed
to react for 3 h at room temperature and then was refluxed
for another 3 h. The resultant mixture was filtered, and the
filtrate was concentrated under reduced pressure. Purification
of the residue by column chromatography (hexane/EtOAc, 1:1,
P en t a ca r b on yl[(3R,4R)-3-et h oxyca r b on yl-4-(2-fu r yl)-
2-a za cyclop en tylid en e]ch r om iu m (22c). Ethyl N-(diphen-
ylmethylidene)glycinate (1.71 g, 6.4 mmol) in THF (20 mL)
was treated at -78 °C with LDA prepared from i-Pr2NH (0.80
mL, 6.4 mmol), BuLi (1.6 M in hexane, 6.4 mmol), and THF
(15 mL). After 30 min, a 0.33 M THF solution of carbene
complex 1f (12 mL, 4 mmol) was diluted in THF (20 mL) and
added to the glycinate anionic solution of 2a at -78 °C. The
reaction mixture was stirred for 1 h at low temperature, and
then was successively treated with 50% HBF4 (7 g, 40 mmol)
(37) Lit.8a reports R for its enantiomer: R (589 nm, 25 °C, l ) 1 dm,
c ) 8.67 g dm-3 in 6 M HCl) ) +19.15.

Synthesis of â-Substituted Glutamic Acids
J . Org. Chem., Vol. 64, No. 18, 1999 6565
and Et3N (6.7 mL, 48 mmol) according to the general proce-
dure. Workup of the reaction as described above gave a crude
material containing carbene complex 22c in 92:8 ds. Flash
chromatography of the crude product (hexane/EtOAc, 9:1, 6:1)
afforded 1.05 g (2.6 mmol, 66% yield) of 22c as a yellow solid:
mp 95-96 °C; Rf ) 0.19 (hexane/EtOAc, 6:1); [R]D ) +18.2 (c
0.5, CHCl3); IR (film) ν (cm-1) 3383, 2058, 1930, 1730; 1H NMR
(CDCl3, 300 MHz) δ 9.08 (1 H, br s), 7.37 (1 H, d, J ) 1.3 Hz),
6.33 (1 H, dd, J ) 3.0, 1.7 Hz), 6.17 (1 H, d, J ) 3.0 Hz), 4.74
(1 H, d, J ) 6.1 Hz), 4.30 (2 H, m), 3.78-3.67 (2 H, m), 3.51 (1
H, dd, J ) 22.0, 9.5 Hz), 1.33 (1 H, t, J ) 6.9 Hz); 13C NMR
(CDCl3, 75 MHz) δ 279.1 (C), 222.5 (C), 217.2 (C), 168.4 (C),
152.0 (C), 142.3 (CH), 110.4 (CH), 106.6 (CH), 72.0 (CH), 62.6
(CH2), 58.3 (CH2), 38.9 (CH), 13.9 (CH3); MS m/z 399 (M+, 14),
Gen er a l P r oced u r e for Hyd r olysis of Com p ou n d s 12.
Syn th esis of P yr oglu ta m ic Acid s 21. The corresponding
ethyl pyroglutamate 12 was dissolved in THF, and 2.5 N LiOH
aqueous solution (18 equiv) was added. The reaction mixture
was stirred at room temperature for 8 h. After removal of the
solvents in a rotary evaporator, the aqueous residue was
acidified with 2 N HCl until pH 2-3 and extracted with CH2-
Cl2. The organic phase was dried (Na2SO4) and evaporated
under reduced pressure to give a small amount of the title
compound. Most of the product was obtained from the aqueous
phase by evaporation of the solvent under reduced pressure
and then flash chromatography purification (EtOAc/HCO2H,
100:8) of the residue.
(2R,3S)-3-P h en ylp yr oglu ta m ic Acid (21a ). Compound
12a (94 mg, 0.40 mmol) and 2.5 N LiOH (3 mL, 7.2 mmol)
were stirred in THF (5 mL) for 8 h. The reaction mixture was
worked-up according to the general procedure to give 15 mg
of 21a from the organic phase and 50 mg of 21a after
purification of the aqueous phase (0.31 mmol, 79%): white
solid; [R]D ) -12.5 (c 0.40, MeOH); IR (KBr) ν (cm-1) 3350,
1670, 1635; 1H NMR (MeOH-d4, 200 MHz) δ 7.5 (5H, m), 4.40
(1 H, d, J ) 4.5 Hz), 3.84 (1 H, m), 3.04 (1 H, dd, J ) 17.1, 9.9
Hz), 2.60 (1 H, dd, J ) 17.1, 5.7 Hz); 13C NMR (MeOH-d4, 50
MHz) δ 180.2 (C), 179.3 (C), 145.4 (C), 130.0 (CH), 129.6 (CH),
128.1 (CH), 67.7 (CH), 46.4 (CH), 39.8 (CH2); MS m/z 205 (M+,
343 (M+ - 1 - CO2Et, 6), 287 (M+ - 4CO, 24), 259 (M+
-
5CO, 100). Anal. Calcd for C16H13CrNO8: C, 48.12; H, 3.28;
N, 3.50. Found: C, 48.34; H, 3.57; N, 3.43.
Gen er a l P r oced u r e for Oxid a tion of Am in oca r ben e
Com p lexes 22. Compounds 22 were oxidized following the
same procedure (method A) described above for oxidation of
compounds 4 and 5; however, the greater stability of ami-
nocarbene derivatives made necessary longer reaction times
and/or more equivalents of pyridine N-oxide.
Eth yl (2R,3S)-3-P h en ylp yr oglu ta m a te (12a ). Carbene
complex 22a (0.16 g, 0.39 mmol) was oxidized with pyridine
N-oxide (0.23 g, 2.4 mmol) in THF (40 mL) for 4 d according
to the general procedure. Solvents were evaporated, and the
residue was worked-up as described above. Flash chromatog-
raphy of the crude product (hexane/EtOAc, 1:1, 1:2, EtOAc)
afforded 48.6 mg (0.21 mmol, 53% yield) of 12a as an oil:
Rf ) 0.27 (hexane/EtOAc, 1:1); [R]D ) -47.6 (c 0.55, CHCl3);
IR (film) ν (cm-1) 3229, 1739, 1705; 1H NMR (CDCl3, 300 MHz)
δ 7.41-7.26 (5 H, m), 6.70 (1 H, br s), 4.31-4.11 (3 H, d + m,
J ) 4.6 Hz), 3.73 (1 H, m), 2.89 (1 H, dd, J ) 17.4, 9.4 Hz),
2.55 (1 H, dd, J ) 17.4, 7.1 Hz), 1.27 (3 H, t, J ) 7.3 Hz); 13C
NMR (CDCl3, 75 MHz) δ 176.6 (C), 171.2 (C), 141.7 (C), 128.9
(CH), 127.4 (CH), 126.8 (CH), 62.8 (CH), 61.6 (CH2), 43.8 (CH),
37.8 (CH2), 14.0 (CH3); MS m/z 233 (M+, 24), 160 (M+ - CO2-
Et, 100), 117 (82), 104 (22); HRMS calcd for C13H15NO3
233.1051, found 233.1051.
Eth yl (2R,3R)-3-(2-F u r yl)p yr oglu ta m a te (12c). Carbene
complex 22c (0.27 g, 0.67 mmol) was oxidized with pyridine
N-oxide (0.57 g, 6.08 mmol) in THF (150 mL) for 5 d according
to the general procedure. The reaction mixture was filtered
through Celite and treated again with pyridine N-oxide (0.57
g, 6.08 mmol) for 3 d. Solvents were evaporated under reduced
pressure, and the residue was worked-up as described above.
Flash chromatography of the crude product (hexane/EtOAc,
1:1, EtOAc) afforded 50 mg (0.22 mmol, 33% yield) of 12c as
an oil: Rf ) 0.16 (hexane/EtOAc, 1:1); [R]D ) -47.1 (c 0.92,
CHCl3); IR (film) ν (cm-1) 3229, 1739, 1709; 1H NMR (CDCl3,
200 MHz) δ 7.36 (1 H, dd, J ) 1.8, 0.9 Hz), 7.11 (1 H, br s),
6.31 (1 H, dd, J ) 3.0, 1.8 Hz), 6.19 (1 H, d, J ) 3.0 Hz), 4.32
(1 H, d, J ) 5.5 Hz), 4.23 (2 H, dq), 3.80 (1 H, m), 2.77 (1 H,
dd, J ) 17.1, 8.8 Hz), 2.62 (1 H, dd, J ) 17.1, 7.3 Hz), 1.27 (1
H, t, J ) 7.3 Hz); 13C NMR (CDCl3, 50 MHz) δ 176.1 (C), 170.8
(C), 153.1 (C), 142.0 (CH), 110.2 (CH), 106.1 (CH), 61.7 (CH2),
60.1 (CH), 37.3 (CH), 34.9 (CH2), 13.9 (CH3); MS m/z 223 (M+,
46), 150 (M+ - CO2Et, 100), 94 (M+ - CO2Et - furyl, 89);
HRMS calcd for C11H13NO4 223.0844, found 223.0843.
24), 160 (M+ - CO2H, 100), 117 (68); HRMS calcd for C11H11
NO3 205.0739, found 205.0740.
-
(2R,3R)-3-(2-F u r yl)p yr oglu ta m ic Acid (21c). Compound
12c (99 mg, 0.44 mmol) and 2.5 N LiOH (3.2 mL, 7.9 mmol)
were stirred in THF (4 mL) for 8 h. The reaction mixture was
worked-up according to the general procedure to give after
purification of the aqueous phase 55 mg (0.28 mmol, 65%) of
21c as a white solid: mp 85-86 °C; Rf ) 0.65 (EtOAc/HCO2H,
10:1); [R]D ) -61.3 (c 0.31, MeOH); IR (KBr) ν (cm-1) 3396,
1670, 1628; 1H NMR (DMSO-d6, 200 MHz) δ 8.26 (1 H, s), 7.72
(1 H, d, J ) 1.0 Hz), 6.51 (1 H, dd, J ) 3.3, 1.6 Hz), 6.43 (1 H,
d, J ) 3.3 Hz), 4.20 (1 H, d, J ) 4.0 Hz), 3.81 (1 H, m), 2.73 (1
H, dd, J ) 16.7, 9.2 Hz), 2.43 (1 H, dd, J ) 16.7, 5.5 Hz); 13C
NMR (DMSO-d6, 75 MHz) δ 175.3 (C), 173.1 (C), 154.6 (C),
142.4 (CH), 110.5 (CH), 105.8 (CH), 59.8 (CH), 37.0 (CH), 34.7
(CH2); MS m/z 195 (M+, 23), 149 (M+ - 1 - CO2H, 2), 94 (100);
HRMS calcd for C9H9NO4 195.0531, found 195.0534.
Ack n ow led gm en t. This research was supported by
the Spanish FARMA III Programme (Ministerio de
Industria) and the DGICYT (Grants PB92-1005 and
PB96-0556).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical and spectral data for compounds 1a -
d ,g, 4a -e,g, 5j-l,n , 6j, 7, 8, 9a -c,g, syn-9a , 10a , 11a , rac-
12a ,c, rac-14a , rac-15a , 19b,g, rac-21a ,c, rac-22a -c, rac-24,
rac-25, and 26 and crystallographic experimental section, table
of X-ray crystal data, final fractional coordinates, anisotropic
thermal parameters, bond lengths and angles, and a crystal-
lographic plot for 4h . This material is available free of charge
via the Internet at http://pubs.acs.org.
J O9819739