Solid-phase synthesis of pyridones and pyridopyrazines as peptidomimetic scaffolds.

Article abstract of DOI:10.1021/ol990960u

[formula: see text] We report the syntheses of peptidomimetic opioids containing the core structure N-alkyl-2-alkyl-2,3-dihydro-4-pyridone. By employing imines bound on a solid support and the Danishefsky diene, this [4 + 2] cyclocondensation reaction fac

Full text of DOI:10.1021/ol990960u

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1407-1409
Solid-Phase Synthesis of Pyridones and
Pyridopyrazines as Peptidomimetic
Scaffolds
Christopher J. Creighton, Christoph W. Zapf, Jane H. Bu, and Murray Goodman*
Contribution from the Department of Chemistry and Biochemistry at the UniVersity of
California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093-0343
mgoodman@ucsd.edu
Received August 18, 1999
ABSTRACT
We report the syntheses of peptidomimetic opioids containing the core structure N-alkyl-2-alkyl-2,3-dihydro-4-pyridone. By employing imines
bound on a solid support and the Danishefsky diene, this [4 + 2] cyclocondensation reaction facilitates the synthesis of novel complex
heterocycles. The central reaction is carried out under mild conditions and employs readily available building blocks. In this study we demonstrate
the suitability of N-alkyl-2-alkyl-2,3-dihydro-4-pyridones as a central scaffold for peptidomimetics and establish the scope of this [4 + 2]
cyclocondensation reaction with imino acids on a solid phase. We also combine the synthesis of diketopiperazines with the [4 + 2]
cyclocondensation reaction to form a 9,9a-dihydro-2H-pyrido-[1,2a]-pyrazine-3,8(1,4-dialkyl)dione, a bicyclic molecule containing a pyridopyrazine
core structure.
It is a major focus of our research group to design and
synthesize ligands possessing modified peptide structures
with functional groups recognized at target sites (e.g.,
somatostatins, opioids, or proteases).1 This approach involves
the construction of a nonpeptidic central scaffold to attach
and display the appropriate pharmacophores.2 Replacement
of the peptide backbone results in compounds with enhanced
biostability and bioavailability.3 Such scaffolds also introduce
conformational constraints which provide information on
structure-activity relationships.4,5
For scaffold-bound peptidomimetics synthesized on a
polymer support, it is desirable to carry out the central
reaction in relatively few steps.6 The synthesis should be
amenable to reactions in solution and on solid supports. It
should be carried out under mild reaction conditions and with
readily available building blocks.7 The synthesis of N-alkyl-
(3) Blackburn, B. K.; Lee, A.; Baier, M.; Kohl, B.; Livero, A. G.;
Matamoros, R.; Robarge, K. D.; McDowell, R. S. J. Med. Chem. 1997, 40,
717-729.
(4) Chang, K.; Rigdon, G. C.; Howard, J. L.; McNutt, R. W. J. Pharm.
Exp. Therap. 1993, 267, 852-857.
(1) Sawyer, T. K. Peptidomimetic and Nonpeptide Drug Discovery:
Impact of Structure-Based Drug Design. In Structure Based Drug Design:
Disease, Targets, Techniques and DeVelopment; Veerapandian, P., Ed.;
Marcel Dekker: New York, 1997; pp 559-634.
(2) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.; Leahy,
E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B. J. Am. Chem. Soc. 1992,
114, 9217-9218.
(5) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.; Lubell, W. D.
Tetrahedron 1995, 2937-2940.
(6) For comprehensive reviews on reactions carried out on the solid phase,
see: Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996,
4527-4554. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron
1997, 5643-5678. Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.;
Reese, D. C. Tetrahedron 1998, 15385-15443.
10.1021/ol990960u CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/28/1999

2-alkyl-2,3-dihydro-4-pyridone by the Diels-Alder type
condensation described by Danishefsky and co-workers
meets these requirements.8-10
receptor subtypes. This Letter describes the utility of this [4
+ 2] cyclocondensation reaction for peptidomimetic scaffold
syntheses.
Scaffold-Based Peptidomimetic Opioids. The [4 + 2]
cyclocondensation reaction was employed to synthesize
representative opioid ligands. The pharmacophores associated
with opioid ligands include amino, benzyl, and phenolic
functional groups.14 Scheme 2 illustrates the successful
In this Letter, we establish the scope and breadth of the
[4 + 2] cyclocondensation utilizing natural and unnatural
amino acid imines. We also combine the solid-phase
chemistries of formation of diketopiperazines11 with N-alkyl-
2-alkyl-2,3-dihydro-4-pyridones. The combination of these
chemistries allows for cyclization-cleavage12 of 9,9a-dihy-
dro-2H-pyrido-[1,2a]-pyrazine-3,8(1,4-dialkyl)diones from
the resin. This eliminates the final purification step since
only the desired product cleaves from the resin while
byproducts of the synthesis are either trapped on the resin
or washed away in the step prior to amino deprotection.
Scheme 2a
This [4 + 2] cyclocondensation reaction is carried out by
allowing an amine to condense with an aldehyde in the
presence of a dehydrating agent to form an imine 1 (Scheme
1).13 Imine 1 is then allowed to react with a silyloxydiene
Scheme 1
such as the Danishefsky diene 2 in the presence of a Lewis
acid. The cyclocondensation reaction is carried out at 4 °C
to produce N-alkyl-2-alkyl-2,3-dihydro-4-pyridones 3 with
yields in the 50-95% range.
a (a) H-Gly-OMe, EDC, HOBt, TEA in CH2Cl2, 95%; (b)
DIBAL-H -78 °C, THF quantitative; (c) H-Phe-Wang resin 1:1
CH2Cl2/HC(OCH3)3; (d) the Danishefsky diene, ZnCl2 (0.5 M) in
THF 24 h 4 °C; (e) TFA/ DCM 1:1. RP-HPLC 55% overall, >95%
de.
We have adapted this methodology to generate pyridone
scaffolds in an effort to create molecularly diverse peptido-
mimetic structures. A family of pyridone-based opioid
analogues were synthesized to illustrate the scaffold-based
peptidomimetic approach and to identify lead opioids. These
compounds were subjected to binding assays and were found
to exhibit modest binding and selectivity to the opioid
synthesis of opioid pyridone 8. Using peptide coupling
conditions, Boc-Tyr(tBu)-OH was allowed to react with
H-Gly-OMe to produce dipeptide 4. Aldehyde 5 was
produced in quantitative yield using DIBAL-H at -78 °C
and was immediately condensed with H-Phe-Wang resin in
the presence of trimethyl orthoformate to form imine 6. Imine
6 was allowed to react with the Danishefsky diene in the
presence of ZnCl2 to form pyridone 7.15 Cleavage from the
resin and removal of the Boc and tert-butyl protecting groups
(7) Houghten, R. A.; Nefzi, A.; Ostresh, J. M. Chem. ReV. 1997, 449-
472.
(8) (a) Kerwin, J. F., Jr.; Danishefsky, S. Tetrahedron Lett. 1982, 23,
3739-3742. (b) Danishefsky, S.; Vogel, C. J. Org. Chem. 1986, 51, 3915-
3916. (c) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400-406.
(9) Wang, Y.; Wilson, S. R. Tetrahedron Lett. 1997, 4021-4024.
(10) Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 4444-4451.
(11) Szardenings, A. K.; Burkoth, T. S.; Lu, H. H.; Tien, D. W.;
Campbell, D. A. Tetrahedron 1997, 6573-6593.
(12) Romoff, T. T.; Wang, Y. W.; Campbell, D. A. Synlett 1997, 1341-
1342.
(13) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A.
Tetrahedron Lett. 1995, 2937-29040.
(14) (a) Hughes, J.; Smith, T. W.; Kosterlitz, H. W.; Forthergill, L. A.;
Morgan, B. A.; Morris, H. R. Nature 1975, 577-579. (b) Morley, J. S.
Annu. ReV. Pharmocol. Toxicol. 1980, 81-110.
(15) We explored the syntheses of pyridones using a variety of Lewis
acids. In our hands ZnCl2 performed much better than Yb(OTf)3 as a catalyst
for pyridone formation. A discussion of this study will be published at a
later date.
1408
Org. Lett., Vol. 1, No. 9, 1999

Compounds 8 and 13 were subjected to a [3H]diprenor-
phine competitive binding assay. Compound 8 exhibits a Ki
at the δ opioid receptor of 7 µM and no binding at the µ or
κ receptors. Compound 13 is selective for the µ receptor with
a Ki of 6 µM and exhibits no binding to the δ and κ receptors.
Scheme 3a
Conclusions
We have demonstrated that synthesis of peptidomimetics
containing the core pyridone structure can be accomplished
on a solid support in good yields. This [4 + 2] cyclocon-
densation reaction facilitates the synthesis of complex
heterocycles in very few steps. The central reaction is carried
out under mild conditions utilizing readily available building
blocks. In this study we have shown the suitability of N-alkyl-
2-alkyl-2,3-dihydro-4-pyridones as a central scaffold for
peptidomimetic design. For the case of compound 13 the
scaffold combines diketopiperazine and pyridone formation
prepared on a solid support. To our knowledge this is the
first time these two chemistries have been combined. The
combination of pyridone and diketopiperazine offers a rigid
scaffold amenable to extensive chemical diversity. The
syntheses of peptidomimetic opioids were accomplished as
an illustrative example of the approach. It is our goal to create
new dienes allowing for multiple points of diversity on the
pyridone scaffold and extend the method to other important
ligands including somatostatin, RGD-like structures, and
protease inhibitors.
a (a) DIBAL-H -78 °C in THF; (b) H-Phe-Merrifield resin, 1:1
CH2Cl2/HC(OCH3)3; (c) the Danishefsky diene, ZnCl2 (0.5M) in
THF 24 h 4 °C; (d) TFA/ CH2Cl2 1:1, 12 h, 45% overall, >95%
de.
Acknowledgment. The authors thank Dr. Heather Sings,
Li Zhang, Dr. Jun-etsu Igarashi, and Juiliann Kwak (UCSD)
for their helpful discussions; Dr. Robert DeHaven of the
Adolor Corporation for performing the opioid binding assays;
and Dr. Gary Suizdak of Scripps Research Institute for mass
spectrometry analysis. We also thank The Affymax Research
Institute and the National Institute of Health (NIH-DA
05539) for financial support.
were achieved using TFA to produce opioid pyridone 8 in a
55% yield after RP-HPLC purification.16
Scheme 3 illustrates the synthesis of a peptidomimetic
opioid with a pyridopyrazine scaffold in which pyridone
synthesis is combined with diketopiperazine formation. The
synthesis was initiated by reaction of R-Boc-diaminopropi-
onic acid methyl ester (Boc-Dpr-OMe) with Boc-Tyr(tBu)-
OH to produce 9 in 95% overall yield. Dipeptide 9 was
subjected to DIBAL-H to reduce the ester to aldehyde 10 in
quantitative yield. The crude aldehyde 10 was immediately
condensed with H-Phe-Merrifield resin in the presence of
trimethyl orthoformate to form imine 11. Imine 11 was
allowed to react with the Danishefsky diene in the presence
of ZnCl2 to form pyridone 12. Acidolysis of the Boc
protecting groups initiated cyclization to produce the pyri-
dopyrazine opioid 13 in 45% overall yield. It is important
to note that the cyclization and subsequent cleavage reaction
yielded pure pyridopyrazine (compound13) for the reasons
noted above.17
OL990960U
(17) Compound 13. Synthesis of the pyridopyrazine 13 was initiated
by condensation of Boc-Dpr(Boc-Tyr(tBu))aldehyde 10 (0.51 g, 1.0 mmol)
with H-Phe-Merrifield resin (0.5 g, 0.27 mmol) (the H-Phe-Merrifield resin
was pretreated with three washes of DCM and three washes of trimethyl
orthoformate) in a 3:2 solution of trimethyl orthoformate:DCM for 3 h at
25 °C. The resin-bound imine 11 was washed with anhydrous THF (2 ×
10 mL). The resin was suspended in 8 mL (4 °C) of 0.5 M ZnCl2 in THF.
Immediately, cold Danishefsky diene (1.0 g, 5 mmol) was added to the
reaction vessel and allowed to react for 16 h at 4 °C. The resin containing
the crude pyridone 12 was washed with DCM (2 × 10 mL), with 2% acetic
acid in methanol (2 × 10 mL), and again with DCM (5 × 10 mL). Cleavage
and cyclization were accomplished by allowing neat TFA (10 mL) to react
with the resin-bound pyridone for 30 min at 25 °C. The TFA was collected,
and the resin was suspended in DCM (10 mL) and placed on a wrist action
shaker for 24 h. Pyridopyrazine 13 was extracted from the solid support
with TFA (2 × 10 mL) and DCM (2 × 10 mL) washes. The extracts where
then combined and concentrated on a rotary evaporator to produce 0.0678
g of a yellow oil (45% yield, >95% pure). 1H NMR (500 MHz, DMSO-d6,
δ) 9.36 (s, 1H), 8.48 (t, 1H, J ) 5.5 Hz), 8.10 (s, 3H), 7.7 (s, 1H) 7.2 (m,
5H), 7.0 (d, 2H, J ) 8.0 Hz), 6.8 (d, 1H, J ) 7.5 Hz), 6.7 (d, 2H, J ) 8
Hz), 4.6 (d, 1H, J ) 7.5 Hz), 4.2 (dd, 1H, J ) 6.5 Hz, 8.5 Hz), 3.9 (m,
1H), 3.8 (m, 1H), 3.7 (m, 1H), 3.25 (m, 1H), 3.20 (m, 1H), 3.1 (m, 2H),
3.0 (dd, 1H, J ) 6.0 Hz, 14 Hz), 2.8 (dd, 1H, J ) 8.5 Hz, 14.5 Hz), 2.6
(dd, 1H, J ) 7 Hz, 17.5 Hz), 2.45 (d, 1H, J ) 3.5 Hz), 2.40 (d, 1H, J )
3.9 Hz). tR ) 17 min. HRMS (m/z): [M + Na]+ calcd for C25H28N4O4Na
471.2008, found, 471.1988.
(16) Compound 8: 1H NMR (500 MHz, DMSO-d6, δ) 8.5 (s, 1H), 7.6
(t, 1H, J ) 5.5 Hz), 6.8 (d, 1H, J ) 6.7 Hz), 6.7 (m, 5H), 6.4 (d, 2H, J )
8.0 Hz), 6.2 (d, 1H, J ) 7.5 Hz), 4.3 (d, 1H, J ) 8.0 Hz) 4.1 (dd, 1H, J )
6.3 Hz, 8.2 Hz), 3.6 (m, 3H), 2.9 (m, 2H), 2.8 (m, 2H), 2.75 (m, 2H), 2.1
(dd, 1H J ) 5.2 Hz, 8.3 Hz), 1.9 (d, 8.3). tR ) 12 min. HRMS (m/z): [M
+ Na]+ calcd for C24H27N3O5Na 460.1848, found, 460.1848.
Org. Lett., Vol. 1, No. 9, 1999
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