Formation of dihydropyridone- and pyridone-based peptide analogs through aza-annulation of β-enamino ester and amide substrates with α-amido acrylate derivatives

Article abstract of DOI:10.1021/jo9600520

The aza-annulation of β-enamino ester and amide substrates with the mixed anhydride of 2-acetamidoacrylic acid was used for the efficient construction of highly substituted α-acetamido δ-lactam products. With the α-acetamido substituent, lactam functionality, and γ-carboxylate group, these δ-lactam products represent an interesting class of conformationally restricted dipeptide analogs. The framework of this lactam hub is structurally related to that of an α-amino acid coupled with a β-amino acid. When α-amino esters derived from naturally occurring amino acids were used in the enamine formation step, subsequent aza-annulation led to branched peptide surrogates with two C-termini that extended from a common N-terminus. Oxidation of the aza-annulation products resulted in the generation of a planar system with peptide functionality radiating from the 1, 3, and 5 positions of the pyridone hub. Alternatively, pyridone products could be formed directly from the enamino amides by reaction with 2-phenyl-4-(ethoxymethylene)oxazolone. Subsequent hydrolysis of the acetamido and ester substituents of the N-benzylpyridones was selectively performed to access unique β-amino acid products. Formation of the mixed anhydride of this acid, followed by amide bond formation with the ester of an α-amino acid, allowed extension of the peptide chain from the dihydropyridone structure.

Full text of DOI:10.1021/jo9600520

J . Org. Chem. 1997, 62, 1033-1042
1033
F or m a tion of Dih yd r op yr id on e- a n d P yr id on e-Ba sed P ep tid e
An a logs th r ou gh Aza -An n u la tion of â-En a m in o Ester a n d Am id e
Su bstr a tes w ith r-Am id o Acr yla te Der iva tives
Lars G. Beholz, Petr Benovsky, Donald L. Ward, Nancy S. Barta,† and J ohn R. Stille*,‡
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824-1322
Received J anuary 8, 1996 (Revised Manuscript Received November 11, 1996X)
The aza-annulation of â-enamino ester and amide substrates with the mixed anhydride of
2-acetamidoacrylic acid was used for the efficient construction of highly substituted R-acetamido
δ-lactam products. With the R-acetamido substituent, lactam functionality, and γ-carboxylate group,
these δ-lactam products represent an interesting class of conformationally restricted dipeptide
analogs. The framework of this lactam hub is structurally related to that of an R-amino acid coupled
with a â-amino acid. When R-amino esters derived from naturally occurring amino acids were
used in the enamine formation step, subsequent aza-annulation led to branched peptide surrogates
with two C-termini that extended from a common N-terminus. Oxidation of the aza-annulation
products resulted in the generation of a planar system with peptide functionality radiating from
the 1, 3, and 5 positions of the pyridone hub. Alternatively, pyridone products could be formed
directly from the enamino amides by reaction with 2-phenyl-4-(ethoxymethylene)oxazolone.
Subsequent hydrolysis of the acetamido and ester substituents of the N-benzylpyridones was
selectively performed to access unique â-amino acid products. Formation of the mixed anhydride
of this acid, followed by amide bond formation with the ester of an R-amino acid, allowed extension
of the peptide chain from the dihydropyridone structure.
In tr od u ction
than the natural peptide substrate. An approach to the
construction of peptide mimics has involved the prepara-
tion of R-amino-substituted γ-, δ-, and ꢀ-lactams that
restrict the conformation of the ψ dihedral angle (2, Ni-
CR-Ci-N(i+1)) and apply further constraints on the ω
dihedral angle (2, CR-Ci-N(i+1)-C(R+1)).1,2 The cyclic
structure provides a framework from which a variety of
functional groups can radiate, and a peptide-like amide
functionality is an integral part of the heterocycle that
contains the peptide â-turn conformation mimic.
Further development in the use of δ-lactams as an
approach to peptide mimics has led to the incorporation
of conformationally restricted dipeptide δ-lactams into
longer peptide sequences. Kemp et al., were able to
model the â-turn topology through the use of a tether
between the CR and C(R+1) atoms and demonstrated the
presence of further conformational control through in-
tramolecular hydrogen bonding (3).3 An alternative
approach was developed by Freidinger et al.,4 who
tethered the CR and N(i+1) atoms of dipeptide analogs to
give 4, and a number of conformationally restricted
Freidinger-type R-amino lactams have been prepared. For
example, 5 is an inhibitor of angiotensin converting
enzyme (ACE).5 This type of structure has also been
Inhibition of enzymatic pathways is one of the most
efficient methods employed for the alteration of physi-
ological processes with the use of minimal amounts of
pharmacological agents. For many enzymatic processes,
derivatives of amino acids are either the substrates or
regulatory molecules for the catalytic action of the
enzyme. Complexation of these amino acid-derived
molecules with enzymes is governed by a specific com-
bination of hydrogen bonds and hydrophobic interactions.
As a result, molecular recognition is highly dependent
on both the type of functional groups present and the
topology of the peptide. An important class of secondary
structures often involved in substrate recognition and
binding are the reverse turn conformations (1), which
include such varieties as the â- and γ-turns.1
The importance of secondary peptide structure in the
process of molecular recognition has led to the strategic
design and subsequent synthesis of â-turn mimics.1
These synthetic analogs can be used to examine peptide
folding processes and to probe peptide activity as a
function of conformation. In some cases, these fragments
can exhibit equivalent or even greater biological activity
(2) For
a recent review of â-turn topography, see: Ball, J . B.;
Hughes, R. A.; Alewood, P. F.; Andrews, P. R. Tetrahedron 1993, 49,
3467.
(3) (a) Kemp, D. S.; Sun, E. T. Tetrahedron Lett. 1982, 23, 3759. (b)
Kemp, D. S.; McNamara, P. Tetrahedron Lett. 1982, 23, 3761. (c) Kemp,
D. S.; McNamara, P. E. J . Org. Chem. 1984, 49, 2286.
(4) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooke, J . R.;
Saperstein, R. Science 1980, 210, 656. (b) Freidinger, R. M.; Veber, D.
F.; Hirschmann, R.; Paege, L. M. Int. J . Pept. Protein Res. 1980, 16,
464. (c) Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J . Org. Chem.
1982, 47, 104.
(5) (a) Thorsett, E. D.; Harris, E. E.; Aster, S. D.; Peterson, E. R.;
Snyder, J . P.; Springer, J . P.; Hirshfield, J .; Tristram, E. W.; Patchett,
A. A.; Ulm, E. H.; Vassil, T. C. J . Med. Chem. 1986, 29, 251. (b)
Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Miyamoto, S.;
Koike, H.; Iijima, Y.; Oizumi, K.; Matsushita, Y.; Hata, T. J . Med.
Chem. 1988, 31, 422.
† Division of Organic Chemistry of the American Chemical Society
Graduate Fellowship recipient, sponsored by Pfizer, Inc., 1993-1994.
‡ Present address: Chemical Process Research and Development,
Eli Lilly and Company, Indianapolis, IN 46285-4813.
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
(1) For reviews on conformationally restricted peptidomimetics,
see: (a) Davies, J . S. Amino Acids Pept. 1991, 22, 145. (b) Liskamp,
R. M. J . Recl. Trav. Chim. Pays-Bas 1994, 113, 1.
S0022-3263(96)00052-7 CCC: $14.00 © 1997 American Chemical Society

1034 J . Org. Chem., Vol. 62, No. 4, 1997
Beholz et al.
incorporated into the framework for an analog of Pro-
Leu-Gly-NH2, which serves to modulate the dopaminergic
receptors in the central nervous system,6 and as a
dipeptide isostere for the Phe-His section of aspartic
proteinase substrates.7
Bicyclic indolizidine structures have been used to
construct conformationally restricted dipeptide models
that contain Pro residues. This conceptual approach has
been incorporated into the D-Phe-Pro mimic 6, which has
been used to examine the peptide folding of the type II′
â-turns present in luteinizing hormone-releasing factor,
human growth hormone-releasing factor, gramicidin S,
Leu-enkephalinamide, and a cyclic somatostatin analog.8
The syntheses of potential Pro-Phe and Ala-Pro type II
â-turn mimics,9 as well as the type VI turn Gly6-Pro7
analog 7, which has been incorporated into bradykinin,10
have also been reported.
aza-annulation reaction of â-enamino carbonyl substrate
11 with acrylate derivative 12, formed in situ by the
treatment of sodium 2-acetamidoacrylate with EtO2CCl
(Scheme 1). This methodology has been an efficient tool
for the formation of δ-lactams13 and has been applied to
the synthesis of naturally occurring alkaloids.14 In
addition, this approach has been used for the synthesis
of conformationally restricted â-amino acids.15 With the
use of 2-acetamidoacrylic acid derivative 12, R-acetamido
substituents can be incorporated in the annulation
process to form 13, with structural features that resemble
those of 4 and 5.15b,16 We have found that these systems
offer a great deal of versatility with respect to the
incorporation of R- or â-amino acids, and the direction-
ality of the peptide constituents.17 Oxidation of these
species leads to the formation of highly substituted
pyridone products such as 14. An approach to direct
(11) (a) Goldman, M. E.; Nunberg, J . H.; O’Brien, J . A.; Quintero,
J . C.; Schleif, W. A.; Freund, K. F.; Gaul, S. L.; Saari, W. S.; Wai, J .
S.; Hoffman, J . M.; Anderson, P. S.; Hupe, D. J .; Emini, E. A.; Stern,
A. M. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 6863. (b) Saari, W. S.;
Hoffman, J . M.; Wai, J . S.; Fisher, T. E.; Rooney, C. S.; Smith, A. M.;
Thomas, C. M.; Goldman, M. E.; O’Brien, J . A.; Nunberg, J . H.;
Quintero, J . C.; Schleif, W. A.; Emini, E. A.; Stern, A. M.; Anderson,
P. S. J . Med. Chem. 1991, 34, 2922. (c) Hoffman, J . M.; Wai, J . S.;
Thomas, C. M.; Levin, R. B.; O’Brien, J . A.; Goldman, M. E. J . Med.
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Damewood, J . R., J r.; Edwards, P. D.; Feeney, S.; Gomes, B. C.;
Steelman, G. B.; Tuthill P. A.; Williams, J . C.; Warner, P.; Woolson,
S. A.; Wolanin, D. J .; Veale, C. A. J . Med. Chem. 1994, 37, 3303. (e)
Bernstein, P. R.; Andisik, P.; Bradley, P. K.; Bryant, C. B.; Ceccarelli,
C.; Damewood, J . R., J r.; Earley, R.; Edwards, P. D.; Feeney, S.; Gomes,
B. C.; Kosmider, B. J .; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.;
Veale, C. A.; Williams, J . C.; Wolanin, D. J .; Woolson, S. A. J . Med.
Chem. 1994, 37, 3313.
Similar heterocyclic strategies have been applied to the
synthesis of mono- and bicyclic pyridone derivatives,
which have played an important role in the development
of bioactive compounds for the inhibition of enzymatic
processes.11 A number of representative pyridone deriva-
tives, 8, are effective inhibitors of HIV reverse tran-
scriptase.11a-c Pyridone 9 is a potent (4.5 nM), reversible
nonpeptidic inhibitor of human leukocyte elastase
(HLE).11d,e When fused to a structure resembling proline,
the pyridone unit is an important feature of A58365A
(10), which is an ACE inhibitor for the treatment of
hypertension.12
(12) (a) Mynderse, J . S.; Samlaska, S. K.; Fukuda, D. S.; Du Bus,
R. H.; Baker, P. J . J . Antibiot. 1985, 38, 1003. (b) Hunt, A. H.;
Mynderse, J . S.; Samlaska, S. K.; Fukuda, D. S.; Maciak, G. M.; Kirst,
H. A.; Occolowitz, J . L.; Swartzendruber, J . K.; J ones, N. D. J .
Antibiotics 1988, 41, 771. (c) Fang, F. G.; Danishefsky, S. J . Tetrahe-
dron Lett. 1989, 30, 3621. (d) Wong, P. L.; Moeller, K. D. J . Am. Chem.
Soc. 1993, 115, 11434.
Our approach to the construction of conformationally
restricted peptide analogs and homologs has utilized the
(13) Paulvannan, K.; Stille, J . R. J . Org. Chem. 1992, 57, 5319.
(14) (a) Paulvannan, K.; Schwarz, J . B.; Stille, J . R. Tetrahedron
Lett. 1993, 34, 215. (b) Paulvannan, K.; Stille, J . R. Tetrahedron Lett.
1993, 34, 6673. (c) Paulvannan, K.; Stille, J . R. J . Org. Chem. 1994,
59, 1613. (d) Cook, G. R.; Beholz, L. G.; Stille, J . R. Tetrahedron Lett.
1994, 35, 1669. (e) Cook, G. R.; Beholz, L. G.; Stille, J . R. J . Org. Chem.
1994, 59, 3575.
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8197. (b) Barta, N. S.; Brode, A.; Stille, J . R. J . Am. Chem. Soc. 1994,
116, 6201.
(16) For previous reports of the use of 2-amidoacrylic acid derivatives
in aza-annulation, see: (a) Thyagarajan, B. S.; Gopalakrishnan, P. V.
Tetrahedron 1964, 20, 1051. (b) Meyer, H.; Bossert, F.; Horstmann,
H. J ustus Liebigs Ann. Chem. 1978, 1483. (a) Danieli, B.; Lesma, G.;
Palmisano, G. J . Chem. Soc., Chem. Commun. 1980, 109. (c) Danieli,
B.; Lesma, G.; Palmisano, G. Gazz. Chim. Ital. 1981, 111, 257. (c)
McCabe, R. W.; Young, D. W.; Davies, G. M J . Chem. Soc., Chem.
Commun. 1981, 395. (d) Chiba, T.; Takahashi, T. Chem. Pharm. Bull.
1985, 33, 2731. (e) Chiba, T.; Takahashi, T.; Kaneko, C. Chem. Pharm.
Bull. 1985, 33, 4002. (f) Capps, N. K; Davies, G. M.; Loakes, D.;
McCabe, R. W.; Young, D. W. J . Chem. Soc., Perkin Trans. 1 1991,
3077. (g) Hua, D. H.; Park, J .-G.; Katsuhira, T.; Bharathi, S. N. J .
Org. Chem. 1993, 58, 2144. (h) Kolar, P.; Tisler, M. J . Heterocycl. Chem.
1993, 30, 1253.
(6) Yu, K.-L.; Rajakumar, G.; Srivastava, L. K.; Mishra, R. K.;
J ohnson, R. L. J . Med. Chem. 1988, 31, 1430.
(7) Zydowsky, T. M.; Dellaria, J . F., J r.; Nellans, H. N. J . Org. Chem.
1988, 53, 5607.
(8) (a) Nagai, U.; Sato, K. Tetrahedron Lett. 1985, 26, 647. (b) Sato,
K.; Nagai, U. J . Chem. Soc., Perkin Trans. 1 1986, 1231. (c) Nagai, U.;
Kato, R.; Sato, K.; Ling, N.; Matsuzaki, T.; Tomotake, Y. In Peptides:
Chemistry and Biology, Proceedings of the Tenth American Peptide
Symposium; Marshall, G. R., Ed.; Escom: Leiden, 1988; p 129. (d)
Nagai, U.; Kato, R. In Peptides: Chemistry, Structure and Biology,
Proceedings of the Eleventh American Peptide Symposium; Rivier, J .
E., Marshall, G. R., Eds.; Escom: Leiden, 1990; p 653. (e) Bach, A. C.,
II; Markwalder, J . A.; Ripka, W. C. Int. J . Pept. Protein Res. 1991, 38,
314. (f) Sato, K.; Hotta, M.; Dong, M.-H.; Hu, H.-Y.; Taulene, J . P.;
Goodman, M.; Nagai, U.; Ling, N. Int. J . Pept. Protein Res. 1991, 38,
340. (g) Nagai, U.; Sato, K.; Nakamura, R.; Kato, R. Tetrahedron 1993,
49, 3577.
(9) (a) Moeller, K. D.; Hanau, C. E.; d’Avignon, A. Tetrahedron Lett.
1994, 35, 825. (b) Mueller, R.; Revesz, L. Tetrahedron Lett. 1994, 35,
4091.
(10) (a) Gramberg, D.; Robinson, J . A. Tetrahedron Lett. 1994, 35,
861. (b) Dumas, J .-P.; Germanas, J . P. Tetrahedron Lett. 1994, 35,
1493.

Dihydropyridone- and Pyridone-Based Peptide Analogs
J . Org. Chem., Vol. 62, No. 4, 1997 1035
Sch em e 1. Gen er a l Str a tegy for th e Con str u ction
of Con for m a tion a lly Restr icted P ep tid e An a logs
th r ou gh Aza -An n u la tion
Sch em e 2. F or m a tion of Dip ep tid e An a logs
th r ou gh Aza -An n u la tion of â-En a m in o Ester sa
pyridone formation, which involves the use of 2-phenyl-
4-(ethoxymethylene)oxazolone, is also described.
Resu lts a n d Discu ssion
Aza -An n u la tion w ith â-En a m in o Ester s. The syn-
thesis and oxidation of R-amido lactams was initially
investigated for the â-amino acid homolog of alanine.
Condensation of 15 with BnNH2 (benzylamine) generated
the intermediate â-enamino ester 16a , which was taken
on to the next step without isolation (Scheme 2). Treat-
ment of 16a with 12, the mixed anhydride of 2-acetami-
doacrylic acid, generated in situ by the reaction of
ClCO2Et with sodium 2-acetamidoacrylate, resulted in
the formation of 17a . This aza-annulation procedure
provided an efficient route for the rapid construction of
conformationally restricted dipeptide 17a , with structural
features resembling those of R-Ala-â-Ala.
Dehydrogenation of 17a was performed by two differ-
ent methods (Scheme 2). Transformation of 17a to 18a
was accomplished by heating the substrate with DDQ in
toluene at reflux.18 Alternatively, MnO2 could be em-
ployed to affect the same transformation at reflux in
xylenes.19 In the latter case, a cleaner reaction was
observed with significantly higher yield.
Further modification of the dipeptide analog was
accomplished through standard procedures. Hydrolysis
of both the ester and amide carboxylates provided the
amino acid product 19a (Scheme 2). Pyridone 19a bears
the features of both a γ-amino acid group (3,5 substituent
pattern) and the conformationally restricted dipeptide
R-Ala-â-Ala. Selective hydrolysis of 18a was performed
to give the N-protected dipeptide surrogate 20a . Exten-
sion of the peptide chain with the ethyl ester of (R)-
phenylglycine was accomplished through established pep-
tide coupling protocol to give the tripeptide analog 21.
The cyclic â-enamino ester 16b,20 related in structure
to proline, was also an effective substrate for aza-
annulation with the mixed anhydride of acrylic acid
(Scheme 2).21 Oxidation of the resulting â-enamido ester
17b resulted in efficient aromatization to give 18b.
Hydrolytic removal of functional group protection gave
the corresponding amino acid of the R-Ala-â-Pro dipeptide
analog 19b and could not be performed selectively to give
the intermediate 20b.
Generation of the intermediate â-enamino ester through
conjugate addition of BnNH2 to alkynoate substrates
provided an alternative method for aza-annulation
(Scheme 3). Conjugate addition of BnNH2 to 22a , fol-
lowed by aza-annulation with 12, generated 24a , a
conformationally restricted dipeptide of R-Ala-R-Asp.
Treatment with DDQ in toluene at reflux resulted in
efficient oxidation of 24a to 26.
Conjugate addition of BnNH2 to 22b and 22c provided
a route to Phe and Ser analogs (Scheme 3). When
initiated from 22b, the two-step aza-annulation proce-
dure resulted in the formation of 24b, the protected
derivative of the R-Ala-â-Ser dipeptide, in a fashion
analogous to the formation of 17a from 15. However,
similar reaction of 22c with BnNH2 resulted in divergent
product formation. While the expected tetrasubstituted
enamido ester 24c comprised only 8% of the product
mixture, kinetic deprotonation of the intermediate at the
benzylic position generated the exocyclic enamide 25 as
a 92:8 ratio of products.22
(17) For the importance of â-amino acids, see: (a) Lubell, W. D.;
Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543. (b)
J uaristi, E.; Quintana, D.; Escalante, J . Aldrichim. Acta 1994, 27, 3.
(18) (a) Meyers, A. I.; Nolen, R. L.; Collington, E. W.; Narwid, T.
A.; Strickland, R. C. J . Org. Chem. 1973, 38, 1974. (b) Sano, T.;
Horiguchi, Y.; Tsuda, Y.; Itatani, Y. Heterocycles 1978, 9, 161.
(19) Bonnaud, B.; Bigg, D. C. H. Synthesis 1994, 465.
(20) The synthesis of 16b was accomplished through methods
described in: Celerier, J . P.; Deloisy-Marchalant, E.; Lhommet, G.;
Maitte, P. Org. Synth. 1988, 67, 170.
(21) For other applications of 16b and related compounds for aza-
annulation reactions, see: (a) Danishefsky, S.; Etheredge, S. J . J . Org.
Chem. 1974, 39, 3430. (b) Nagasaka, T.; Inoue, H.; Ichimura, M.;
Hamaguchi, F. Synthesis 1982, 848. (c) Nagasaka, T.; Inoue, H.;
Hamaguchi, F. Heterocycles 1983, 20, 1099. (d) Brunerie, P.; Ce´le´rier,
J .-P.; Huche´, M.; Lhommet, G. Synthesis 1985, 735. (e) ref 12c. (f) Shen,
W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J . J . Org. Chem.
1993, 58, 611. (g) Reference 14c. (h) Reference 15a.

1036 J . Org. Chem., Vol. 62, No. 4, 1997
Beholz et al.
Sch em e 3. F or m a tion of r-Ala -â-P h e, r-Ala -A-Asp ,
a n d r-Ala -â-Ser Dip ep tid e An a logs fr om Acetylen ic
Ester sa
Sch em e 4a F or m a tion of P ep tid e An a logs th r ou gh
Aza -An n u la tion a n d P yr id on e F or m a tion fr om
â-Keto Am id esb
Ta ble 1. F or m a tion of P ep tid e An a logs th r ou gh
Aza -An n u la tion a n d P yr id on e F or m a tion fr om â-Keto
Am id esa
isolated yield
product
R1
Ph
Ph
EtO2C
EtO2C
R2
28 to 30
30 to 31
a
b
c
d
H
90
76
55
78
60
CO2Et
H
CO2Et
87b
95
86b
a
Tabulated results for Scheme 4. b 51:49 ratio of diastereomers.
Aza -a n n u la tion w ith â-En a m in o Am id es. The aza-
annulation reaction of 12 with intermediate â-enamino
amide 29a , generated from â-keto amide 28a (R1 ) Ph),
resulted in efficient formation of the heterocyclic product
30a (Scheme 4). The corresponding oxidation of the
enamido amide derivatives was substantially more slug-
gish than that of the related ester substrates.18 In fact,
dehydrogenation was typically incomplete and required
a second treatment with DDQ to increase conversion to
product. The use of xylenes as the solvent in place of
toluene, or the use of increased equivalents of DDQ or
MnO2, did not provide an increased yield of product
(Table 1). Despite the lower reactivity of 30a toward
oxidation, the dipeptide analog 31a was still obtained in
respectable yield.
A higher level of complexity in these systems was
accessed through condensation of 28a with the ethyl ester
of (R)-phenylglycine (Scheme 4, Table 1). Aza-annulation
of the intermediate â-enamino amide 29b with 12
resulted in the formation of 30b as an equal mixture of
diastereomers (51:49). This two-step procedure served
to rapidly construct a complex heterocyclic product in
87% yield from the three basic components 28b, 2-ac-
etamidoacrylic acid, and (R)-phenylglycine ethyl ester.
As was observed for 30a , DDQ oxidation of 30b generated
the amide-substituted pyridone system 31b, but the
reaction was not as facile as that of the related ester
Opportunities for further modification of 24c and 25
were somewhat limited (Scheme 3). Treatment of these
products under the same conditions used to oxidize 17
to 18 did not result in oxidation of these substrates to
the corresponding pyridone products. Instead, reaction
of 24b with DDQ under standard conditions, even for
extended periods of time, resulted only in the recovery
of unreacted 24b. Similar reaction of 25 under the
established DDQ oxidation conditions resulted only in
alkene isomerization to produce an 80:20 mixture of 24c:
25, while only a trace of the corresponding pyridone
product was observed.23 Isolation and subsequent treat-
ment of 24c with DDQ under standard conditions still
did not result in pyridone formation. An alternative
means of product modification, hydrogenation of 25,
produced 27 as a 96:4 ratio of only two diastereomers,
for which rigorous stereochemical assignment was not
made. Presumably, hydrogen added to the double bond
from the side opposite that of the ester functionality,
which provided 27 with a cis relationship between the
groups at C-5 and C-6. The 94:6 ratio reflects a mixture
of isomers at C-3.
(22) Nuclear Overhauser enhancement (NOE) studies on 25 were
used to confirm that the stereochemistry of the double bond for the
major isomer was E. Irradiation of the vinyl proton resulted in the
enhancement of the N-benzyl protons of 3.3% and 1.6%. The relation-
ship of the minor and major isomers, whether isomeric in alkene
geometry or cis/trans diasteromers, was not established.
(23) The 80:20 composition of the reaction mixture was determined
by 1H NMR. Characteristic peaks of 24c were the following: 2.49 (td,
J ) 15.9, 3.0 Hz, 1 H), 3.55 (dd, J ) 15.9, 6.3 Hz, 1 H), 4.63 (dt, J )
15.1, 6.3 Hz, 1 H).

Dihydropyridone- and Pyridone-Based Peptide Analogs
J . Org. Chem., Vol. 62, No. 4, 1997 1037
Sch em e 5. Deter m in a tion of Ep im er iza tion
substrates. Oxidation with MnO2 resulted in only 50%
conversion of 30b to 31b after 48 h at reflux in xylenes.19
Compounds 31a and 31b represent an interesting class
of conformationally restricted peptide-like molecules.
Peptide functional groups, both amino and carboxylate
functionality, radiate from the 1, 3, and 5 positions of
the pyridone hub. The amide functionality of the pyri-
done heterocycle displays structural features present in
peptide derived molecules. Combination of the 1 and 5
substituents reflect the structural features of a linear
dipeptide, while the 3 and 5 positions are similar to those
found in conformationally bent peptide chains. Interest-
ingly, the relationship between the 1 and 5 positions is
one in which both an R and a â amino acid radiate from
a common nitrogen atom.
d u r in g Aza -An n u la tion a n d Oxid a tion Rea ction sa
Efficient aza-annulation was observed with substrate
28c (R1 ) CO2Et), which was readily obtained by the
reaction of diketene with glycine ethyl ester (Scheme 4,
Table 1). Formation of â-enamino amide 29c, followed
by aza-annulation, gave the tripeptide analog 30c in 95%
yield for the two-step process from 28c. Oxidation of 30c
proceeded in a fashion similar to that of 30b, and two
treatments with DDQ were required to accumulate a
yield of 78%. Condensation of 28c with (R)-phenylglycine
ethyl ester generated 29d , which gave 30d as an equal
mixture of diastereomers (51:49) upon aza-annulation
with 12. Oxidation of 30d with DDQ in toluene at reflux
generated the pyridone hub with amino acid functionality
radiating from the 1, 3, and 5 positions.
In order to probe the compatibility of the aza-annula-
tion reaction conditions with the stereochemical integrity
of the amino acid components, lactam and pyridone
products that contained two separate sites of asymmetry
were formed. Condensation of 32 was performed sepa-
rately with valine- and phenylglycine-derived esters to
give 33 and 36, respectively (Scheme 5). In each case,
examination of the intermediate enamine showed the
presence of a single diastereomer. Aza-annulation with
sodium acrylate/ClCO2Et under standard reaction condi-
tions led to the conversion of 33 to 34a as a single
diastereomer (>98:2 by NMR analysis of the crude
reaction mixture). Similarly, treatment with sodium
2-acetamidoacrylate/ClCO2Et led to an 89% yield of 34b,
which was a 50:50 mixture of diastereomers at the 3
position of the lactam, but did not result in epimerization
of the amino acid groups. Conversion of 36 to 37 also
was accomplished as a single diastereomer. Based on
these observations, epimerization of the amino acid
stereocenters did not occur under the aza-annulation
conditions.
Oxidation of 34 was dependent on the nature of the
substituent at the 3 position of the lactam. When R )
H, treatment of 34a or 37 with DDQ led to a mixture of
products which did not contain significant quantities of
the desired pyridone products. However, when a 2-ac-
etamido substituent was present (34b), oxidation resulted
in the formation of 35b as a single diastereomer. How-
ever, this reaction could not be driven to complete
conversion without significant degradation of the desired
product. After two sequential treatments with DDQ, the
product was isolated in 40% yield, which represented a
59% yield based on recovered 34b. The generation of a
single stereoisomer demonstrated that the stereochemical
integrity of the amino acid groups was maintained during
the oxidation process.
crystalline solid, which allowed for the single crystal
X-ray analysis of this molecule.27 The ORTEP represen-
tation of this molecule is shown in Figure 1. There are
several features of this structure that are worth com-
ment. In addition to structure confirmation, the orienta-
tion and interactions of the peptide-like chains at the 3
and 5 positions of the lactam ring, and the effects that
the N-benzyl substitutent has on the packing of this
molecule are interesting.
Although intramolecular hydrogen bonding in solution
cannot be ruled out, the ORTEP representation of this
molecule clearly illustrates an absence of intramolecular
hydrogen bonding in the solid state. However, several
intermolecular hydrogen bonding interactions were ob-
served in this crystal lattice between the amide substit-
uents at the 3 and 5 positions of the lactam heterocycle.
As a result of these interactions, a “ladder” type struc-
tural feature was observed (Figure 2). The perspective
in Figure 2 contains four molecules of 30c, and the
N-benzyl substituents have been omitted for clarity.
From this representation, the alternating orientations of
Str u ctu r a l An a lysis of 30c. During the course of
these studies, R-amido lactam 30c was obtained as a

1038 J . Org. Chem., Vol. 62, No. 4, 1997
Beholz et al.
Sch em e 6. Dir ect P yr id on e F or m a tion th r ou gh
Aza -An n u la tion a
Dir ect F or m a tion of P yr id on es. The use of 2-phen-
yl-4-(ethoxymethylene)oxazolone (39), an alternative re-
agent for aza-annulation, was explored for the direct
formation of pyridone products (Scheme 6). Reagent 39
was readily prepared from hippuric acid by reaction with
ethyl orthoformate in acetic anhydride as previously
reported.24 Although aza-annulation of enamino esters
and amides with this reagent had been reported to
proceed in dioxane with added NEt3 at 85 °C,24 analogous
reaction of enamino amide 38 with 39, with or without
NEt3, resulted primarily in the formation of 40. Cycliza-
tion of 40 to 41 was affected eventually by an increase
in reaction temperature; when a solution of 40 was
heated to reflux in DMF, complete conversion to 41 was
achieved. This aza-annulation process was performed in
a single procedure by treatment of 38 with 39 in DMF
followed by reflux of the reaction mixture. The low
isolated yields obtained for 41, especially when compared
to yields obtained for similar reaction of 39 with either
33 or 42, were a consequence of the generation of reaction
byproducts that were difficult to remove during isolation
of 41.
F igu r e 1. ORTEP, line representations, and numbering
scheme of structural data obtained for 30c.
Aza-annulation of 42, derived from 32, resulted in more
efficient ring formation to give 43 (Scheme 7). Isolation
and analysis of 43 led to some interesting properties of
1
these molecules in solution. Initial H NMR analysis of
43 in CDCl3 revealed a 70:30 ratio of two sets of
resonances. However, systematic dilution of 43 resulted
in conversion of this mixture into predominantly one set
of peaks (90:10). This concentration dependent phenom-
ena has been observed before with peptides, and has been
attributed to intermolecular hydrogen bonding of these
molecules, which becomes less prevalent upon increased
dilution.25
F igu r e 2. Intermolecular hydrogen bonding observed for 30c.
N-Benzyl groups have been omitted for clarity.
the ring system necessary to adopt this lattice is appar-
ent, as is the directionality of the ladder.
These intermolecular hydrogen bond interactions were
found between O(10) and H(13)-N(13), with distances
of 1.794 and 1.045 Å for the O---H and H-N bonds,
respectively. The O---H-N angle observed for this
interaction was 158.5°, which is typical for hydrogen
bonding geometry. Similarly, O(19) and H(8)-N(8)
interactions were evident between two molecules of 30c,
with distances of 1.951 and 0.919 Å for the O---H and
H-N bonds, respectively. A value of 161.6° was observed
for the O---H-N angle of this hydrogen bond.
Enamine 33, formed as a single diastereomer as
determined by 1H NMR, was used to determine the
extent to which epimerization occurred as a result of the
(24) Behringer, H.; Taul, H. Chem. Ber. 1957, 90, 1398.
(25) (a) Dobashi, A.; Saito, N.; Motoyama, Y.; Hara, S. J . Am. Chem.
Soc. 1986, 108, 307. (b) J ursic, B. S.; Goldberg, S. I. J . Org. Chem.
1992, 57, 7172.

Dihydropyridone- and Pyridone-Based Peptide Analogs
J . Org. Chem., Vol. 62, No. 4, 1997 1039
Sch em e 7. Deter m in a tion of Ep im er iza tion
d u r in g Dir ect P yr id on e F or m a tion a
chain. The enamine product could then either react in
an intermolecular manner with an electrophile at the
active site or intramolecularly revert to the lactam.
Synthetic oxidation of the δ-lactams leads to pyridone
peptide analogs, which would be inert to typical condi-
tions for peptide hydrolysis. As possible peptide mimet-
ics, these compounds have the potential to interfere with
biochemical events that would lead to significant biologi-
cal effects. The biological activity of these molecules is
currently being examined and will be reported separately.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all reactions
were carried out using standard inert atmosphere techniques
to exclude moisture and oxygen, and reactions were performed
under an atmosphere of nitrogen. Xylenes and decalin were
heated over calcium hydride for a minimum of 12 h and then
distilled prior to use. LiAlH4 (1 M in THF) was obtained from
Aldrich Chemical Co. MnO2 was used without purification
(Fisher Scientific).
Dehydration of condensation reactions was performed with
the use of a modified Dean-Stark apparatus in which the
cooled distillate was passed through 4-Å molecular sieves prior
to return of the solvent to the reaction mixture.26 The sieves
were changed during reactions in which additional reagent was
added after reaction had progressed.
Gen er a l Meth od for th e F or m a tion of â-Keto Am id es.
Diketene (5.0-30.0 mmol, 1.0 equiv), BnNH2 or HCl‚H2NCH2-
CO2Et (1.0 equiv), and NaHCO3 (2.0 equiv) were combined in
benzene (0.5 M solution of amine) at 0 °C. The mixture was
warmed to room temperature, stirred for 14 h, and then
filtered. Removal of solvent under reduced pressure gave the
product as a solid, and crystallization from Et2O/CHCl3 yielded
the product as white leaflets.
28a : 3.59 g, 18.8 mmol, 81% yield; mp 100-102 °C; 1H NMR
(300 MHz, CDCl3) δ 2.24 (s, 3 H), 3.42 (s, 2 H), 4.44 (d, J )
6.0 Hz, 2 H), 7.25-7.40 (m, 6 H); 13C NMR (75 MHz, CDCl3)
δ 30.90, 43.46, 49.56, 127.42, 127.62, 128.62, 137.88, 165.38,
204.35; IR (KBr) 3249, 3085, 1715, 1640, 1443, 1410, 1190,
1163 cm-1; HRMS calcd for C11H13NO2 m/ z 191.0146, obsd
m/ z 191.0982.
aza-annulation process with 39 (Scheme 7). The reaction
of 42 with 39, generated by condensation of (S)-valine
methyl ester with 32, resulted in an 81% yield of 44 for
the two-step condensation/aza-annulation process. Al-
though this procedure provided an efficient route the
rapid construction of a complex molecule from readily
available starting materials, the diastereomer ratio that
was produced in this reaction sequence was only 86:14.
During this aza-annulation process, some epimerization
had occurred at the sites of asymmetry due to the high
temperature (154 °C) required for heterocycle formation.
Su m m a r y. The aza-annulation reaction provides an
efficient route for the potential construction of the
heterocyclic framework for complex bioactive compounds
such as natural product targets or synthetic peptide
mimetics. With this method, peptide analogs as complex
as 31d can be assembled in three steps in 52% overall
yield, and the aza-annulation process with acrylate
derivatives did not proceed with epimerization. The
resulting compounds contain δ-lactam peptide-like bonds,
which exhibit restricted rotation of both ψ and ω dihedral
angles. These angles can be altered by oxidation of the
dihydropyridone (ψ ) 166°) to the pyridone (ψ ) 180°).
However, during the oxidation process, significant epimer-
ization of the R-amino acid derivatives (20%) was ob-
served. The pyridone substituents can be completely
deprotected to give the corresponding amino acid, or can
be selectively hydrolyzed to generate the R-amido car-
boxylic acid.
1
28c: 1.74 g, 9.35 mmol, 99% yield; mp 52-53 °C; H NMR
(300 MHz, CDCl3) δ 1.28 (t, J ) 7.1 Hz, 3 H), 2.28 (s, 3 H),
3.50 (s, 2 H), 4.04 (d, J ) 5.4 Hz, 2 H), 4.20 (q, J ) 7.2 Hz, 2
H), 7.61 (bs, 1 H); 13C NMR (75 MHz, CDCl3) δ 13.84, 30.36,
41.11, 49.63, 61.13, 166.16, 169.41, 203.54; IR (KBr) 3353,
2986, 1754, 1715, 1673, 1543, 1418, 1401, 1321, 1175 cm-1
;
HRMS calcd for C8H13NO4 m/ z 187.0845, obsd m/ z 187.0844.
32: Noncrystalline, purified by column chromatography,
eluent: 50:50/diethyl ether:petroleum ether, 3.27 g, 15.2 mmol,
1
85% yield; H NMR (300 MHz, CDCl3) δ 0.85 (d, J ) 7.2 Hz,
3 H), 0.89 (d, J ) 7.2 Hz, 3 H), 2.12 (m, 1 H), 2.21 (s, 3 H),
3.43 (s, 2 H), 3.66 (s, 3 H), 4.46 (dd, J ) 5.0, 8.6 Hz, 1 H), 7.48
(bd, J ) 8.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 17.5, 18.8,
30.5, 30.8, 49.5, 51.9, 57.1, 165.8, 172.0, 203.9; IR (neat) 3320,
2967, 2878, 1746, 1653, 1541, 1437, 1360, 1267, 1156 cm-1
;
HRMS calcd for C10H17NO4 m/ z 215.1158, obsd m/ z 215.1149.
Gen er a l Meth od for th e Aza -An n u la tion of â-Keto
Am id es a n d â-Keto Ester s. (R)-Phenylglycine ethyl ester
hydrochloride salt was suspended in benzene (1.5 mL/mmol
of substrate) and washed with saturated aqueous NaHCO3.
After the aqueous layer was washed with benzene (10 mL),
the benzene layers were combined, washed with saturated
aqueous NaCl, and dried (MgSO4). The benzene solution was
then used without further manipulation.
A mixture of the BnNH2 or phenylglycine ethyl ester (0.5-
5.0 mmol, 1.0 equiv) and the â-keto amide or â-keto ester (1.0
equiv) were taken up in benzene (0.5 M relative to the
As potential bioprocess substrates, these conforma-
tionally restricted heterocyclic peptide analogs would be
expected to show unique properties at the active site of
enzymatic reactions. Hydrolysis of the enamides would
lead to the generation of a nucleophilic enamine, but
would not result in the fragmentation of the substrate
(26) Barta, N. S.; Paulvannan, K.; Schwarz, J . B.; Stille, J . R. Synth.
Commun. 1994, 24, 853.
(27) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

1040 J . Org. Chem., Vol. 62, No. 4, 1997
Beholz et al.
substrate), and BF3‚OEt2 (0.5 equiv) was added. The reaction
vessel was fitted with a modified distillation apparatus for
azeotropic removal of H2O,26 and the reaction was heated at
reflux until complete as determined by NMR analysis (6-18
h). The solvent was then removed under reduced pressure,
and the crude enamine was brought up in THF (0.1 M). The
mixture was cooled to -78 °C, and the sodium salt of
2-acetamidoacrylic acid (1.3 equiv) was added. EtO2CCl (1.3
equiv) was then added, and the reaction mixture was warmed
to room temperature and stirred until complete (≈14 h).
Saturated aqueous NaHCO3 was then added, and the mixture
was extracted with EtOAc. The combined organic fractions
were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography (Et2O/EtOAc/MeOH).
30d : mixture of diastereomers, ratio 49:51; 0.52 g, 1.13
mmol, 86% yield; mp 77-80 °C (mixture); 1H NMR (300 MHz,
CDCl3, characteristic peaks) δ (major isomer) 2.03 (s, 3 H),
2.12 (d, J ) 1.5 Hz, 3 H), 2.45 (btq, J ) 9.0, 1.5 Hz, 1 H), 2.77
(ddd, J ) 7.8, 3.3, 1.5 Hz, 1 H), 5.62 (s, 1 H), 6.17 (bt, J ) 2.9
Hz, 1 H), (minor isomer) 2.02 (s, 3 H), 2.24 (d, J ) 1.5 Hz, 3
H), 2.33 (btq, J ) 9.0, 1.5 Hz, 1 H), 3.10 (ddd, J ) 9.0, 3.3, 1.5
Hz, 1 H), 5.68 (s, 1 H), 6.13 (bt, J ) 2.9 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ 13.97, 16.29, 16.56, 22.75, 22.98, 28.16, 28.26,
41.35, 41.42, 46.44, 49.04, 59.71, 59.91, 60.78, 61.32, 61.80,
62.35, 100.38, 113.15, 113.52, 167.73, 127.71, 127.77, 127.99,
128.04, 128.09, 128.20, 128.34, 133.26, 134.22, 134.44, 139.46,
139.49, 140.42, 167.92, 168.04, 168.47, 169.04, 169.30, 169.35,
169.40, 169.74, 169.79, 170.22, 170.30, 171.05; IR (KBr) 3277,
2986, 1744, 1655, 1541, 1204 cm-1; HRMS calcd for C23H29N3O7
m/ z 459.2006, obsd m/ z 459.2011.
17a : 0.56 g, 1.70 mmol, 74% yield; mp 132-135 °C; 1H NMR
(300 MHz, CDCl3) δ 1.28 (t, J ) 7.2 Hz, 3 H), 2.06 (s, 3 H),
2.27 (tq, J ) 15.9, 2.6 Hz, 1 H), 2.37 (d, J ) 2.1 Hz, 3 H), 3.40
(dd, J ) 15.9, 6.3 Hz, 1 H), 4.17 (q, J ) 7.2 Hz, 2 H), 4.55 (dt,
J ) 14.7, 6.0 Hz, 1 H), 4.78 (d, J ) 16.1 Hz, 1 H), 5.22 (d, J )
16.1 Hz, 1 H), 6.61 (bd, J ) 5.1 Hz, 1 H), 7.11 (d, J ) 6.9 Hz,
2 H), 7.22-7.36 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ 14.14,
16.11, 23.15, 27.69, 45.80, 48.96, 60.51, 109.12, 126.04, 127.41,
127.63, 128.83, 136.73, 147.35, 166.68, 170.12; IR (KBr) 3299,
2986, 1686, 1389, 1248, 1163 cm-1; HRMS calcd for C18H22N2O4
m/ z 330.1580, obsd m/ z 330.1572.
34a : 48:48:4/diethyl ether:petroleum ether:methyl alcohol;
0.53 g, 1.39 mmol, 60% yield; 1H NMR (300 MHz, CDCl3) δ
0.74 (d, J ) 7.1 Hz, 3 H), 0.86 (d, J ) 6.8 Hz, 3 H), 0.90 (d, J
) 6.9 Hz, 3 H), 1.08 (d, J ) 6.4 Hz, 3 H), 2.16 (m, 1 H), 2.14
(s, 3 H), 2.38-2.53 (m, 4 H), 2.61 (m, 1 H), 3.60 (s, 3 H), 3.69
(s, 3 H), 4.03 (bd, J ) 8.5 Hz, 1 H), 4.55 (dd, J ) 4.9, 8.5 Hz,
1 H), 5.93 (d, J ) 8.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ
16.5, 17.9, 18.9, 19.1, 22.0, 22.2, 28.0, 31.2, 52.0, 52.1, 57.0,
61.2, 113.2, 140.5, 168.8, 170.2, 170.6, 172.5; IR (CHCl3) 3316,
2969, 2876, 1746, 1657, 1524, 1437, 1399, 1304, 1267 cm-1
;
17b: 1.27 g, 4.77 mmol, 74% yield; mp 150-151 °C; 1H NMR
(300 MHz, CDCl3) δ 1.29 (t, J ) 7.2 Hz, 3 H), 2.03 (quint, J )
7.3 Hz, 2 H), 2.07 (s, 3 H), 2.29 (tt, J ) 15.6, 2.9 Hz, 1 H), 3.16
(td, J ) 7.7, 2.1 Hz, 2 H), 3.40 (dd, J ) 16.2, 7.5 Hz, 1 H), 3.68
(dt, J ) 11.4, 7.3 Hz, 1 H), 3.79 (dt, J ) 11.4, 7.2 Hz, 1 H),
4.19 (q, J ) 7.2 Hz, 2 H), 4.54 (dt, J ) 14.4, 7.2, 1 H), 6.39 (d,
J ) 5.7 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.33, 21.59,
23.17, 27.99, 31.20, 46.17, 49.60, 60.15, 100.82, 152.30, 166.41,
167.89, 170.23; IR (KBr) 3281, 2984, 2849, 1690, 1642, 1545,
1399, 1248, 1173, 1109 cm-1; HRMS calcd for C13H18N2O4 m/ z
266.1267, obsd m/ z 266.1260.
HRMS calcd for C19H30N2O6 m/ z 382.2104, obsd m/ z 382.2098.
34b: 90:5:5; Et2O/petroleum ether/MeOH; 2.73 g, 6.21 mmol,
89% yield, 50:50 mixture of diastereomers; mp ) 69-70 °C
sealed, dec; 1H NMR (300 MHz, CDCl3) δ 0.74 (d, J ) 7.2 Hz,
3 H), 0.75 (d, J ) 7.2 Hz, 3 H), 0.85-0.94 (m, 12 H), 1.09 (d,
J ) 7.2 Hz, 3 H), 1.11 (d, J ) 7.2 Hz, 3 H), 1.96 (s, 3 H), 1.97
(s, 3 H), 2.06 (d, J ) 1.8 Hz, 3 H), 2.09-2.20 (m, 2 H), 2.20 (d,
J ) 1.8 Hz, 3 H), 2.24-2.42 (m, 2 H), 2.48-2.68 (m, 2 H), 2.91
(dd, J ) 6.3, 15.3 Hz, 1 H), 2.99 (dd, J ) 6.3, 15.3 Hz, 1 H),
3.61 (s, 3 H), 3.64 (s, 3 H), 3.69 (s, 6 H), 3.95 (d, J ) 8.7 Hz, 1
H), 4.26 (bs, 1 H), 4.35-4.57 (m, 4 H), 6.19 (d, J ) 8.7 Hz, 1
H), 6.42 (d, J ) 8.4 Hz, 1 H), 6.56 (d, J ) 5.7 Hz, 1 H), 6.61 (d,
J ) 5.7 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 11.5, 11.7, 13.16,
13.24, 14.2, 14.4, 17.0, 17.4, 18.2, 22.9, 23.5, 23.6, 23.8, 26.1,
26.4, 44.0, 44.3, 47.3, 47.4, 47.5, 52.5, 52.6, 56.9, 57.4, 107.9,
108.7, 134.0, 136.1, 162.8, 163.3, 164.4, 164.5, 164.8, 165.4,
165.5, 165.9, 167.5, 167.6; IR (CHCl3) 3308, 3011, 2969, 1742,
1653, 1534, 1437, 1269, 1244 cm-1; HRMS calcd for C21H33N3O7
m/ z 439.2319, obsd m/ z 439.2285.
1
30a : 0.78 g, 2.06 mmol, 90% yield; mp 82-85 °C; H NMR
(300 MHz, CDCl3) δ 1.92 (s, 3 H), 2.07 (d, J ) 2.3 Hz, 3 H),
2.41 (btd, J ) 15.3, 2.3 Hz, 1 H), 2.93 (dd, J ) 15.5, 6.4 Hz, 1
H), 4.35 (dd, J ) 14.7, 5.5 Hz, 1 H), 4.43 (dd, J ) 14.7, 5.5 Hz,
1 H), 4.54 (dt, J ) 15.0, 6.4 Hz, 1 H), 4.63 (d, J ) 16.4 Hz, 1
H), 5.05 (d, J ) 16.4 Hz, 1 H), 6.80 (bt, J ) 5.7 Hz, 1 H), 6.98
(bd, J ) 6.3 Hz, 1 H), 7.07 (d, J ) 6.6 Hz, 2 H), 7.16-7.30 (m,
8 H); 13C NMR (75 MHz, CDCl3) δ 15.87, 22.79, 28.51, 43.44,
45.45, 48.78, 112.45, 125.86, 127.15, 127.57, 128.39, 128.61,
136.82, 138.02, 139.12, 167.80, 169.27, 170.21; IR (KBr) 3289,
3002, 1734, 1659, 1584, 1543, 1321, 1248 cm-1; HRMS calcd
for C23H25N3O3 m/ z 391.1896, obsd m/ z 391.1895.
37: 48:48:4/diethyl ether:petroleum ether:methyl alcohol,
1
0.29 g, 0.68 mmol, 49% yield; mp ) 44-45 °C; H NMR (300
MHz, CDCl3) δ 0.85 (d, J ) 6.9 Hz, 3 H), 0.90 (d, J ) 6.8 Hz,
3 H), 1.21 (t, J ) 7.1 Hz, 3 H), 2.06 (s, 3 H), 2.12 (m, 1 H),
2.40-2.55 (m, 2 H), 2.55-2.66 (m, 2 H), 3.69 (s, 3 H), 4.18 (q,
J ) 7.1 Hz, 2 H), 4.55 (dd, J ) 4.8, 8.6 Hz, 1 H), 5.60 (s, 1 H),
5.84 (bd, J ) 8.6 Hz, 1 H), 7.05-7.33 (m, 5 H); 13C NMR (75
MHz, CDCl3) δ 14.1, 16.8, 17.9, 22.2, 31.2, 31.4, 52.2, 57.1,
59.8, 61.7, 114.1, 126.1, 128.0, 128.4, 128.7, 135.0, 140.1, 168.7,
168.8, 170.6, 172.5; IR (CHCl3) 3324, 2967, 1744, 1659, 1522,
1395, 1374, 1302, 1262, 1156, 1028 cm-1; HRMS calcd for
C23H30N2O6 m/ z 430.2104, obsd m/ z 430.2105.
30b: mixture of diastereomers, ratio 49:51; 0.36 g, 0.80
mmol, 87% yield; mp 83-85 °C (mixture); 1H NMR (300 MHz,
CDCl3, characteristic peaks) δ (major isomer) 2.01 (s, 3 H),
2.22 (d, J ) 1.2 Hz, 3 H), 2.30 (bdt, J ) 9.2, 1.5 Hz, 1 H), 5.67
(s, 1 H), 5.92 (m, 1 H), (minor isomer) 2.02 (s, 3 H), 2.10 (d, J
) 1.2 Hz, 3 H), 2.43 (btd, J ) 9.2, 1.5 Hz, 1 H), 5.59 (s, 1 H),
5.95 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 13.87, 16.22, 16.50,
20.86, 22.78, 28.17, 28.33, 40.42, 43.46, 46.47, 48.94, 59.82,
61.67, 111.05, 113.61, 114.01, 117.30, 126.02, 127.06, 127.17,
127.50, 127.55, 127.71, 127.95, 128.21, 128.37, 128.41, 128.52,
134.26, 134.42, 137.88, 137.95, 138.52, 139.39, 167.46, 167.64,
168.02, 168.43, 169.22, 169.61, 170.13, 170.18; IR (KBr) 3297,
3007, 1742, 1651, 1532, 1217 cm-1; HRMS calcd for C26H29N3O5
m/ z 463.2107, obsd m/ z 463.2150.
Gen er a l Met h od for t h e F or m a t ion of Acet ylen ic
Ester s. To 3-(benzyloxy)propyne or 3-phenylpropyne (10-50
mmol, 1.0 equiv, 0.5 M in THF) at -78 °C was added n-BuLi
(1.0 equiv, 2.5 M in hexane). After 10 min, EtO2CCl (1.5 equiv)
was added dropwise. The reaction mixture containing 3-phe-
nylpropyne was slowly warmed to room temperature, and the
mixture was stirred for 14 h. In the case of 3-(benzyloxy)-
propyne, the reaction was promptly quenched as soon as a deep
red color began to form in the solution. Each reaction was
quenched by addition of H2O, the organic layer was removed,
and the solvent was removed under reduced pressure. The
crude oils were purified by flash column chromatography
(petroleum ether).
1
30c: 1.06 g, 2.74 mmol, 95% yield; mp 71-74 °C; H NMR
(300 MHz, CDCl3) δ 1.25 (t, J ) 7.1 Hz, 3 H), 2.00 (s, 3 H),
2.16 (d, J ) 2.2 Hz, 3 H), 2.46 (btd, J ) 15.3, 2.2 Hz, 1 H),
2.96 (dd, J ) 15.3, 6.5 Hz, 1 H), 3.95 (dd, J ) 18.1, 5.6 Hz, 1
H), 4.04 (dd, J ) 18.1, 5.6 Hz, 1 H), 4.14 (q, J ) 7.2 Hz, 2 H),
4.59 (dt, J ) 15.3, 6.5 Hz, 1 H), 4.67 (d, J ) 16.7 Hz, 1 H),
5.13 (d, J ) 16.7 Hz, 1 H), 6.91 (t, J ) 5.6 Hz, 1 H), 7.05-7.13
(m, 3 H), 7.19-7.34 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ
13.84, 15.79, 22.78, 28.31, 41.18, 45.42, 48.74, 61.09, 111.95,
125.82, 127.12, 128.58, 136.78, 139.74, 168.09, 169.34, 169.69,
170.25; IR (KBr) 3285, 2984, 1744, 1657, 1584, 1543, 1319,
1190 cm-1; HRMS calcd for C20H25N3O5 m/ z 387.1794, obsd
m/ z 387.1789.
22b: 1.61 g, 7.45 mmol, 91% yield; 1H NMR (300 MHz,
CDCl3) δ 1.29 (t, J ) 7.2 Hz, 3 H), 4.22 (q, J ) 7.2 Hz, 2 H),
4.25 (s, 2 H), 4.59 (s, 2 H), 7.22-7.40 (m, 5 H); 13C NMR (75
MHz, CDCl3) δ 13.78, 56.53, 61.90, 71.81, 78.07, 82.94, 127.87,
127.90, 128.29, 136.59, 152.87; IR (oil/NaCl) 3032, 2984, 2872,
2236, 1713, 1248 cm-1
.

Dihydropyridone- and Pyridone-Based Peptide Analogs
J . Org. Chem., Vol. 62, No. 4, 1997 1041
1
22c: 3.06 g, 16.28 mmol, 94% yield; 1H NMR (300 MHz,
CDCl3) δ 1.30 (t, J ) 7.1 Hz, 3 H), 3.73 (s, 2 H), 4.23 (q, J )
7.1 Hz, 2 H), 7.25-7.40 (m, 5 H); 13C NMR (75 MHz, CDCl3)
δ 14.00, 24.97, 61.87, 74.84, 86.20, 127.16, 127.99, 128.69,
18b: 0.039 g, 0.150 mmol, 78% yield; mp 225-226 °C; H
NMR (300 MHz, CDCl3) δ 1.33 (t, J ) 7.1 Hz, 3 H), 2.18 (s, 3
H), 2.21 (quint, J ) 7.7 Hz, 2 H), 3.50 (t, J ) 7.7 Hz, 2 H),
4.16 (t, J ) 7.7 Hz, 2 H), 4.28 (q, J ) 7.1 Hz, 2 H), 8.14 (bs, 1
H), 8.85 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.31, 20.99,
24.63, 33.04, 49.43, 60.78, 106.11, 122.55, 126.13, 149.57
156.83, 164.86, 168.80; IR (KBr) 3297, 2982, 2936, 1715, 1684,
1636, 1532, 1196, 1100 cm-1; HRMS calcd for C13H16N2O4 m/ z
264.1110, obsd m/ z 264.1108.
134.07, 153.67; IR (oil/NaCl) 2984, 2238, 1709, 1255 cm-1
.
Gen er a l Meth od for th e Aza -An n u la tion of Acetylen ic
Ester s. A mixture of BnNH2 (0.5-5.0 mmol, 1.0 equiv) and
acetylenic ester (1.0 equiv) was taken up in THF (0.5 M
relative to the amine), and BF3‚OEt2 (0.5 equiv) was added.
The mixture was stirred at ambient temperature until the
reaction had gone to completion, as indicated by 1H NMR. The
solvent was removed under reduced pressure, and the crude
enamine was taken up in THF (0.1 M). The mixture was
cooled to -78 °C, and the sodium salt of 2-acetamidoacrylic
acid (1.3 equiv) was added to the enamine. EtO2CCl (1.3
equiv) was then added, and the reaction mixture was warmed
to room temperature and stirred until complete (≈14 h).
Saturated aqueous NaHCO3 was added, and the mixture was
extracted with EtOAc. The combined organic fractions were
dried over Na2SO4 and filtered, and the solvent was evaporated
under reduced pressure. The crude product was purified by
flash column chromatography (Et2O/EtOAc/MeOH).
26: 0.21 g, 0.59 mmol, 71% yield; mp ) 128-129 °C; 1H
NMR (300 Hz, CDCl3) δ 2.19 (s, 3 H), 3.79 (s, 3 H), 3.85 (s, 3
H), 5.26 (s, 2 H), 7.19-7.32 (m, 5 H), 8.34 (bs, 1 H), 8.84 (s, 1
H); 13C NMR (75 MHz, CDCl3) δ 24.67, 50.44, 52.62, 53.41,
109.06, 120.06, 127.36, 128.04, 128.61, 128.83, 134.77, 138.14,
157.02, 163.12, 164.18, 169.23; IR (KBr) 3374, 3021, 2955,
1728, 1691, 1645, 1516, 1437, 1215 cm-1; HRMS calcd for
C18H18N2O6 m/ z 358.1165, obsd m/ z 358.1153.
31a : 0.21 g, 0.56 mmol, 76% yield; mp 180-181 °C; 1H NMR
(300 MHz, acetone-d6) δ 2.10 (s, 3 H), 2.42 (s, 3 H), 4.55 (d, J
) 6.0 Hz, 2 H), 5.51 (s, 2 H), 7.12-7.16 (m, 2 H), 7.19-7.56
(m, 8 H), 8.18 (t, J ) 6.0 Hz, 1 H), 8.54 (s, 1 H), 8.96 (s, 1 H);
13C NMR (75 MHz, acetone-d6) δ 17.28, 24.36, 44.20, 48.79,
108.50, 122.42, 127.30, 127.83, 128.13, 128.45, 129.21, 129.51,
129.60, 136.99, 137.25, 145.43, 158.59, 168.47, 169.97; IR (KBr)
3299, 3067, 3034, 2880, 1705, 1634, 1507, 1476, 1248, 1003
cm-1; HRMS calcd for C23H23N3O3 m/ z 389.1739, obsd m/ z
389.1762.
24a : 3.60 g, 10.0 mmol, 71% yield; mp 151-154 °C; 1H NMR
(300 MHz, CDCl3) δ 2.05 (s, 3 H), 2.34 (dd, J ) 16.3, 15.6 Hz,
1 H), 3.42 (dd, J ) 16.3, 7.0 Hz, 1 H), 3.67 (s, 3 H), 3.73 (s, 3
H), 4.63 (ddd, J ) 15.6, 7.0, 5.6 Hz, 1 H), 4.65 (d, J ) 15.6 Hz,
1 H), 4.94 (d, J ) 15.6 Hz, 1 H), 6.51 (bd, J ) 5.6 Hz, 1 H),
7.16-7.22 (m, 2 H), 7.25-7.36 (m, 3 H); 13C NMR (75 MHz,
CDCl3) δ 23.07, 26.41, 47.81, 48.43, 52.24, 52.90, 108.95,
127.13, 127.79, 128.56, 135.77, 141.88, 163.32, 165.05, 169.21,
170.14; IR (KBr) 3306, 2953, 1742, 1705, 1634, 1534, 1437,
1248 cm-1; HRMS calcd for C18H20N2O6 m/ z 360.1322, obsd
m/ z 360.1308.
1
31b: 0.16 g, 0.35 mmol, 55% yield; mp ) 155-156 °C; H
NMR (300 MHz, CDCl3) δ 1.24 (t, J ) 7.2 Hz, 3 H), 2.18 (s, 3
H), 2.50 (s, 3 H), 4.26 (q, J ) 7.2 Hz, 2 H), 4.57 (dd, J ) 5.6,
1.7 Hz, 2 H), 6.12 (s, 1 H), 6.19 (m, 1 H), 7.19-7.43 (m, 10 H),
8.27 (s, 1 H), 8.53 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.10,
17.52, 24.67, 44.28, 62.11, 62.69, 116.21, 120.69, 126.86,
127.73, 127.85, 128.15, 128.54, 128.62, 128.85, 133.01, 137.69,
139.77, 140.51, 167.20, 167.38, 169.27; IR (KBr) 3280, 2960,
2920, 1736, 1647, 1516, 1455, 1217 cm-1; HRMS calcd for
C26H27N3O5 m/ z 461.1951, obsd m/ z 461.1901.
1
24b: 3.32 g, 7.61 mmol, 83% yield; mp 97-99 °C; H NMR
(300 MHz, CDCl3) δ 1.26 (t, J ) 7.2 Hz, 3 H), 2.03 (s, 3 H),
2.29 (td, J ) 16.0, 2.0 Hz, 1 H), 3.39 (dd, J ) 16.0, 6.6 Hz, 1
H), 4.16 (q, J ) 7.2 Hz, 2 H), 4.31 (dd, J ) 12.9, 2.0 Hz, 1 H),
4.45 (dt, J ) 15.0, 6.0 Hz, 1 H), 4.54 (d, J ) 12.0 Hz, 1 H),
4.60 (d, J ) 12.0 Hz, 1 H), 4.80 (d, J ) 16.5 Hz, 1 H), 5.00 (d,
J ) 12.9 Hz, 1 H), 5.41 (d, J ) 16.5 Hz, 1 H), 6.73 (bd, J ) 5.7
Hz, 1 H), 6.98-7.02 (m, 2 H), 7.17-7.38 (m, 8 H); 13C NMR
(75.5 MHz, CDCl3) δ 13.97, 22.99, 28.00, 45.62, 48.50, 60.90,
63.07, 72.50, 112.97, 125.91, 127.16, 127.87, 128.32, 128.64,
137.12, 137.39, 145.35, 165.91, 170.07; IR (KBr) 3310, 3011,
2936, 1673, 1632, 1497, 1392, 1372, 1217 cm-1; HRMS calcd
for C25H28N2O5 m/ z 436.1998, obsd m/ z 436.2064.
1
31c: 0.31 g, 0.15 mmol, 80% yield; mp ) 177-180 °C; H
NMR (300 MHz, acetone-d6) δ 1.21 (t, J ) 7.1 Hz, 3 H), 2.11
(s, 3 H), 2.48 (s, 3 H), 4.10 (d, J ) 6.0 Hz, 2 H), 4.13 (q, J ) 7.1
Hz, 2 H), 5.54 (s, 2 H), 7.14-7.17 (m, 2 H), 7.24-7.56 (m, 3
H), 8.01 (t, J ) 6.0 Hz, 1 H), 8.54 (s, 1 H), 9.04 (s, 1 H); 13C
NMR (75 MHz, acetone-d6) δ 14.42, 17.22, 24.38, 42.21, 48.85,
61.47, 108.55, 122.56, 127.30, 129.21, 129.52, 129.62, 137.19,
145.59, 158.65, 168.80, 170.10, 170.28; IR (KBr) 3277, 3032,
1748, 1671, 1644, 1512, 1210, 1003 cm-1; HRMS calcd for
C20H23N3O5 m/ z 385.1638, obsd m/ z 385.1623.
25: mixture of isomers, ratio 92:8; 2.64 g, 6.5 mmol, 61%
1
1
yield; H NMR (300 MHz, CDCl3) δ 1.14 (t, J ) 7.1 Hz, 3 H),
31d : 0.32 g, 0.70 mmol, 60% yield; mp ) 204-205 °C; H
1.79 (ddd, J ) 13.1, 11.1, 6.6 Hz, 1 H), 2.03 (s, 3 H), 2.80 (ddd,
J ) 13.1, 9.4, 7.0 Hz, 1 H), 3.85-4.87 (m, 3 H), 4.47 (dt, J )
11.1, 6.3 Hz, 1 H), 4.77 (d, J ) 15.4 Hz, 1 H), 5.23 (d, J ) 15.4
Hz, 1 H), 6.46 (s, 1 H), 6.84 (d, J ) 5.8 Hz, 1 H), 7.13-7.38
(m, 5 H); 13C NMR (75.5 MHz, CDCl3) δ 13.84, 23.00, 29.05,
40.78, 48.71, 51.43, 61.38, 121.37, 127.32, 127.47, 128.40,
128.51, 128.90, 134.38, 135.82, 137.00, 169.53, 170.00, 171.91;
NMR (300 MHz, CDCl3) δ 1.24 (t, J ) 7.2 Hz, 3 H), 1.28 (t, J
) 7.2 Hz, 3 H), 2.17 (s, 3 H), 2.49 (s, 3 H), 4.13-4.29 (m, 6 H),
6.14 (s, 1 H), 6.55 (bs, 1 H), 7.26-7.48 (m, 5 H), 8.32 (s, 1 H),
8.55 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.08, 17.53, 24.54,
41.88, 61.74, 62.17, 62.65, 112.68, 115.71, 121.15, 126.60,
128.08, 128.59, 128.92, 132.86, 134.72, 140.19, 157.78, 167.40,
167.67, 169.65; IR (KBr) 3314, 2986, 1744, 1645, 1524, 1217,
1082, 1003 cm-1; HRMS calcd for C23H27N3O7 m/ z 457.1849,
obsd m/ z 457.1853.
IR (KBr) 3330, 2982, 1734, 1671, 1496, 1410, 1244, 1184 cm-1
;
HRMS calcd for C24H26N2O4 m/ z 406.1893, obsd m/ z 406.1920.
Gen er a l Meth od for th e DDQ Oxid a tion of Aza -An n u -
la tion P r od u cts. A mixture of the aza-annulation product
(0.5-50.0 mmol, 1.0 equiv) and DDQ (1.5 equiv) was taken
up in toluene (0.1 M with respect to the aza-annulation
product). After heating at reflux for 14 h, the solvent was
removed under reduced pressure, and the crude product was
purified by flash column chromatography (Et2O/EtOAc) or
crystallized (CHCl3/EtOAc). For compounds derived from
â-keto amides, the oxidation was repeated to acquire the
indicated yields.
35b: 90:5:5; Et2O/petroleum ether/MeOH; 0.20 g, 0.46 mmol,
1
40% yield; mp ) 90-91 °C sealed, dec.; H NMR (300 MHz,
CDCl3) δ 0.63 (d, J ) 6.9 Hz, 3 H), 0.97 (d, J ) 6.9 Hz, 3 H),
1.01 (d, J ) 6.9 Hz, 3 H), 1.24 (d, J ) 6.9 Hz, 3 H), 2.13 (s, 3
H), 2.19-2.32 (m, 2 H), 2.49 (bs, 3 H), 3.60 (s, 3 H), 3.76 (s, 3
H), 4.32 (bs, 1 H), 4.65 (dd, J ) 4.5, 8.7 Hz, 1 H), 6.45 (d, J )
8.7 Hz, 1 H), 8.19 (bs, 1 H), 8.53 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 17.6, 17.8, 18.9, 19.1, 22.2, 24.4, 26.8, 31.2, 52.2, 52.3,
57.6, 64.9, 115.5, 120.8, 126.3, 139.6, 157.2, 167.5, 168.9, 169.1,
172.1; IR (CHCl3) 3305, 3015, 2971, 2876, 1748, 1653, 1611,
1522, 1215 cm-1; HRMS calcd for C21H31N3O7 m/ z 437.2162,
obsd m/ z 437.2158.
1
18a : 0.029 g, 0.088 mmol, 58% yield; mp 176-178 °C; H
NMR (300 MHz, CDCl3) δ 1.37 (t, J ) 7.1 Hz, 3 H), 2.19 (s, 3
H), 2.68 (s, 3 H), 4.30 (q, J ) 7.1 Hz, 2 H), 5.47 (s, 2 H), 7.09
(d, J ) 6.7 Hz, 2 H), 7.26-7.35 (m, 3 H), 8.30 (bs, 1 H), 8.91
(s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.19, 16.91, 24.63, 48.33,
61.15, 110.44, 122.64, 125.77, 126.05, 127.64, 128.94, 135.22,
145.30, 158.40, 165.88, 169.02; IR (KBr) 3308, 2982, 1713,
1638, 1516, 1192 cm-1; HRMS calcd for C18H20N2O4 m/ z
328.1423, obsd m/ z 328.1411.
Oxid a tion of 17a w ith Mn O2. Compound 17a (0.28g, 0.89
mmol) and MnO2 (0.46g, 5.3 mmol) were combined and
suspended in xylenes (20 mL). The mixture was heated under
an air atmosphere with azeotropic removal of H2O for 16 h.26
After the reaction mixture was cooled to room temperature,
the solution was filtered through Celite and concentrated in
vacuo. Purification was accomplished via flash column chro-

1042 J . Org. Chem., Vol. 62, No. 4, 1997
Beholz et al.
matography (80:20 EtOAc/petroleum ether) to give 18a (0.25
g, 0.80 mmol) in 90% yield.
1642, 1541, 1455, 1217 cm-1; HRMS calcd for C24H28N2O4 m/ z
408.2049, obsd m/ z 408.2075.
Gen er a l Met h od for t h e Hyd r olysis of E st er s a n d
Am id es. A mixture of the pyridone (0.5-2.0 mmol, 1.0 equiv)
and KOH (20.0 equiv) was taken up in H2O (for hydrolysis of
esters) or 30% H2O2 (for hydrolysis of amides) (0.1 M with
respect to the pyridone). After 14 to 38 h, the reaction was
extracted with CHCl3, filtered, and neutralized with HCl.
Compound 20a was collected by filtration, and the unprotected
amino acids (19a and 19b) were collected by solvent removal
under reduced pressure followed by extraction with MeOH or
acetone. The products were then crystallized (MeOH/CHCl3
or MeOH/Et2O).
Gen er a l Meth od for Aza -An n u la tion w ith 39. The
corresponding enamine (0.78-2.6 mmol) was dissolved in
anhydrous DMF (0.26 M) and 39 (1.0 equiv) was added. After
the reaction mixture was heated to reflux for 2 h, the dark
brown solution was concentrated to an oil (boiling water bath),
and the crude product was purified by flash column chroma-
tography (SiO2, 230-400 mesh, Et2O/petroleum ether/MeOH
) 48:48:4).
41: 0.18 g, 0.38 mmol, 49% yield; 1H NMR (300 MHz, CDCl3)
δ 0.57 (d, J ) 6.9 Hz, 3 H), 1.20 (d, J ) 6.3 Hz, 3 H), 2.50 (s,
3 H), 2.93 (m, 1 H), 3.61 (s, 3 H), 4.32 (m, 1 H), 4.49 (dd, J )
14.7, 5.7 Hz, 1 H), 4.54 (dd, J ) 15.6, 5.7 Hz, 1 H), 6.67 (bt, J
) 5.1 Hz, 1 H), 7.16-7.32 (m, 5 H), 7.32-7.41 (m, 2 H), 7.46
(m, 1 H), 7.74-7.81 (m, 2 H), 8.59 (s, 1 H), 8.95 (bs, 1 H); 13C
NMR (75 MHz, CDCl3) δ 17.8, 18.9, 22.2, 26.8, 44.2, 52.4, 65.0,
115.9, 121.0, 126.2, 127.0, 127.6, 127.9, 128.7, 132.3, 133.6,
137.8, 140.0, 157.5, 165.8, 167.4, 169.0; IR (CHCl3) 3372, 3015,
2971, 1750, 1638, 1611, 1582, 1520, 1491, 1389, 1275, 1215,
1024 cm-1; HRMS calcd for C27H29N3O5 m/ z 475.2107, obsd
(M + 1) m/ z 476.2174.
1
19a : 0.047 g, 0.183 mmol, 61% yield; mp 205-206 °C; H
NMR (300 MHz, DMSO-d6) δ 2.46 (s, 3 H), 5.46 (s, 2 H), 7.07-
7.54 (m, 5 H), 8.02 (s, 1 H); 13C NMR (75 MHz, DMSO-d6) δ
16.83, 30.74, 115.41, 127.05, 128.34, 129.37, 129.86, 133.98,
135.86, 137.69, 160.60, 169.74; IR (KBr) 2928, 1709, 1640,
1549, 1455, 1256, 1024 cm-1; HRMS calcd for C14H14N2O3 m/ z
258.1004, obsd m/ z 258.0987.
1
20a : 0.48 g, 2.03 mmol, 61% yield; mp >260 °C; H NMR
(300 MHz, acetone-d6) δ 2.07 (s, 3 H), 2.70 (s, 3 H), 5.55 (s, 2
H), 7.17 (d, J ) 6.9 Hz, 1 H), 7.26-7.35 (m, 4 H), 8.98 (s, 1 H);
13C NMR (75 MHz, acetone-d6) δ 17.09, 24.32, 48.52, 106.25,
123.00, 127.10, 128.14, 129.62, 130.55, 133.29, 137.24, 158.84,
167.42, 171.53; IR (KBr) 3277, 3031, 1692, 1622, 1603, 1553,
1387, 1190 cm-1; HRMS calcd for C16H16N2O4 m/ z 300.1110,
obsd m/ z 300.1096.
43: 0.62 g, 1.31 mmol, 71% yield; 1H NMR (300 MHz, CDCl3)
δ 0.85 (d, J ) 6.9 Hz, dimer), 0.89 (d, J ) 6.9 Hz, dimer), 1.00
(d, J ) 6.8 Hz, 3 H), 1.01 (d, J ) 6.8 Hz, 3 H), 2.08 (m, dimer),
2.17 (s, dimer), 2.20 (s, 3 H), 2.24 (m, 1 H), 3.63 (s, dimer),
3.70 (s, 3 H), 4.44 (dd, J ) 8.5, 5.1 Hz, dimer), 4.56 (dd, J )
8.5, 5.2 Hz, 1 H), 5.03 (bd, J ) 15.7 Hz, 1 H), 5.31 (bd, J )
15.7 Hz, 1 H), 6.99 (d, J ) 6.6 Hz, 2 H), 7.12-7.24 (m, 3 H),
7.34-7.52 (m, 3 H), 7.82 (d, J ) 7.8 Hz, 2 H), 8.63 (s, 1 H),
9.09 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 16.6, 17.6, 18.1,
18.9, 19.1, 30.8, 48.3, 52.0, 52.1, 57.0, 57.9, 58.0, 115.65, 115.70,
121.0, 121.1, 125.8, 125.9, 126.2, 127.0, 127.2, 127.6, 128.6,
128.8, 132.1, 133.4, 133.5, 135.0, 140.0, 158.0, 158.1, 165.55,
165.63, 167.7, 167.8, 171.9, 172.1; IR (neat) 3306, 2967, 1744,
1646, 1522, 1210, 1154 cm-1; HRMS calcd for C27H29N3O5 m/ z
475.2107, obsd (M + 1) m/ z 476.2172.
1
19b: 0.061 g, 0.314 mmol, 82% yield; H NMR (300 MHz,
DMSO-d6) δ 2.03 (quint, J ) 7.6 Hz, 2 H), 3.25 (t, J ) 7.6 Hz,
2 H), 3.95 (t, J ) 7.6 Hz, 2 H), 6.91 (s, 1 H); 13C NMR (75
MHz, DMSO-d6) δ 21.09, 32.45, 48.73, 111.03, 128.51, 129.14,
135.41, 143.12, 156.81; IR (KBr) 3364, 1698, 1615, 1536, 1117
cm-1; HRMS calcd for C9H10N2O3 m/ z 194.0692, obsd m/ z
194.0681.
F or m a tion of 21a . To a solution of 20a (0.20 g, 0.85 mmol)
in THF (8.5 mL) was added NaH (0.92 g, 0.85 mmol) at -78
°C. EtO2CCl (0.081 mL, 0.85 mmol) was added to the reaction
mixture followed by (R)-phenylglycine ethyl ester (0.183 g, 0.85
mmol). The reaction was warmed to room temperature and
was stirred for 2 h. Saturated aqueous NaHCO3 (excess) was
added, and the mixture was extracted with EtOAc. The
combined organic fractions were dried over Na2SO4 and
filtered, and the solvent was evaporated under reduced pres-
sure. The crude product was purified by flash column chro-
matography (Et2O/EtOAc/MeOH) to give 21a (0.29 g, 0.66
mmol, 78% yield): mp 209-210 °C; 1H NMR (300 MHz, CDCl3)
δ 1.22 (t, J ) 7.1 Hz, 3 H), 2.17 (s, 3 H), 2.42 (s, 3 H), 4.17 (dq,
J ) 10.7, 7.1 Hz, 1 H), 4.25 (dq, J ) 10.7, 7.1 Hz, 1 H), 5.38 (s,
2 H), 5.63 (d, J ) 7.1 Hz, 1 H), 6.98 (d, J ) 7.1 Hz, 1 H), 7.09
(d, J ) 6.5 Hz, 2 H), 7.25-7.44 (m, 8 H), 8.37 (s, 1 H), 8.55 (s,
1 H); 13C NMR (75 MHz, CDCl3) δ 13.90, 16.88, 24.43, 48.53,
57.22, 61.99, 126.20, 126.31, 127.33, 127.63, 128.49, 128.57,
128.84, 128.96, 135.02, 135.89, 140.32, 157.95, 166.84, 169.61,
44: 0.75 g, 1.50 mmol, 81% yield; 1H NMR (300 MHz, CDCl3)
δ 0.50 (d, J ) 6.6 Hz, 3 H), 0.80-0.90 (m, minor), 0.94 (d, J )
7.9 Hz, 3 H), 0.98 (d, J ) 7.9 Hz, 3 H), 1.17 (d, J ) 6.3 Hz, 3
H), 2.08 (m, minor), 2.21 (m, 1 H), 2.43 (s, 3 H), 2.88 (m, 1 H),
3.60 (s, 3 H), 3.62 (s, minor), 3.70 (s, 3 H), 4.29 (bd, J ) 6.3
Hz, 1 H), 4.43 (dd, J ) 8.3, 5.0 Hz, minor), 4.58 (dd, J ) 8.3,
5.0 Hz, 1 H), 6.89 (bd, J ) 6.6 Hz, 1 H), 7.30-7.50 (m, 3 H),
7.80 (d, J ) 7.1 Hz, 2 H), 8.49 (s, minor), 8.66 (s, 1 H), 8.95
(bs, 1 H), 9.67 (bs, minor); 13C NMR (75 MHz, CDCl3) δ 17.6
(minor), 18.0, 18.8 (minor), 19.0, 22.0 (minor), 30.8 (minor),
31.0, 49.3 (minor), 51.9 (minor), 52.1, 52.3, 57.1 (minor), 57.8,
115.7, 121.0, 126.2, 127.0, 127.3 (minor), 128.4 (minor), 128.6,
128.8 (minor), 132.1, 133.6, 139.6, 165.6, 167.6, 172.1; IR (neat)
3366, 3305, 2969, 1742, 1640, 1613, 1516, 1389, 1380, 1271,
1210 cm-1; HRMS calcd for C26H33N3O7 m/ z 499.2319, obsd
m/ z 499.2323.
170.58; IR (KBr) 3324, 3019, 1736, 1636, 1514, 1217 cm-1
;
Ack n ow led gm en t. Support from the National In-
stitutes of Health (GM44163) is gratefully acknowl-
edged. Spectral product characterization was performed
on NMR instrumentation purchased in part with funds
from NIH grant 1-S10-RR04750 and from NSF grant
CHE-88-00770. The assistance of Susan Reutzel and
Victoria Russell was invaluable for the structural
analysis of 30c. N.S.B. wishes to thank the Organic
Division of the American Chemical Society and Pfizer,
Inc., for a Division of Organic Chemistry Graduate
Fellowship, and the General Electric Co. for an Aca-
demic Incentive Fellowship.
HRMS calcd for C26H27N3O5 m/ z 461.1951, obsd m/ z 461.1939.
F or m a tion of 27. Enamine 25 (0.24 g, 1.05 mmol) was
dissolved in EtOH (10.5 mL), and Na2CO3 (0.39 g, 3.67 mmol)
and 10% Pd/C (0.10 g) were added. The reaction mixture was
placed under an atmosphere of H2. After stirring for 16 h,
the reaction mixture was filtered, and the solvent was removed
under reduced pressure. The resulting crude oil was purified
by flash column chromatography (Et2O). Removal of solvent
gave a white solid, which was crystallized from EtOAc to give
27 as a mixture of diastereomers (96:4 product ratio, 0.23 g,
1
0.99 mmol, 94% yield): mp 202-205 °C; H NMR (300 MHz,
CDCl3) (major diastereomer) δ 1.16 (t, J ) 7.2 Hz, 3 H), 2.00
(s, 3 H), 2.32 (q, J ) 13.7 Hz, 1 H), 2.55 (m, 1 H), 2.93 (dt, J
) 13.7, 4.4 Hz, 1 H), 3.21 (dd, J ) 13.7, 7.4 Hz, 1 H), 3.29 (d,
J ) 15.2 Hz, 1 H), 3.90 (dq, J ) 10.8, 7.1 Hz, 1 H), 4.01 (dq, J
) 10.8, 7.1 Hz, 1 H), 4.07 (m, 2 H), 5.24 (d, J ) 15.2 Hz, 1 H),
7.00 (dd, J ) 7.5, 1.9 Hz, 2 H), 7.12 (d, J ) 6.4 Hz, 1 H), 7.21-
7.34 (m, 8 H); 13C NMR (75 MHz, CDCl3) (major diastereomer)
δ 13.92, 22.87, 25.69, 37.30, 42.80, 49.65, 50.81, 58.76, 60.95,
126.77, 127.37, 127.47, 128.51, 128.57, 129.34, 136.80, 138.09,
169.14, 170.45, 170.52; IR (solid/NaCl) 3297, 3067, 3009, 1732,
Su p p or tin g In for m a tion Ava ila ble: X-ray data for struc-
ture 30c, and copies of NMR spectra of isolated products (39
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9600520