Efficient, stereoselective synthesis of oxazolo[3,2-a]pyrazin-5-ones: Novel bicyclic lactam scaffolds from the bicyclocondensation of 3-aza-1,5-ketoacids and amino alcohols

Article abstract of DOI:10.1021/ol030065h

(Matrix presented) The bicyclocondensation of 3-aza-1,5-ketoacids and amino alcohols furnished novel oxazolo[3,2-a]pyrazin-5-one scaffolds possessing angular, ring junction substituents in high yield with excellent levels of substrate-based diastereocontr

Full text of DOI:10.1021/ol030065h

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2727-2730
Efficient, Stereoselective Synthesis of
Oxazolo[3,2-a]pyrazin-5-ones: Novel
Bicyclic Lactam Scaffolds from the
Bicyclocondensation of
3-Aza-1,5-ketoacids and Amino Alcohols
Josef R. Bencsik, Timothy Kercher,* Michael O’Sullivan, and John A. Josey
Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301
tim.kercher@arraybiopharma.com
Received May 28, 2003
ABSTRACT
The bicyclocondensation of 3-aza-1,5-ketoacids and amino alcohols furnished novel oxazolo[3,2-a]pyrazin-5-one scaffolds possessing angular,
ring junction substituents in high yield with excellent levels of substrate-based diastereocontrol. Mild oxidation of serinol-derived scaffolds
provided access to a new class of constrained dipeptide surrogates. Deprotection of the endocyclic amine contained within these scaffolds
allows for further diversification via N-functionalization.
The use of peptides as drugs has generally been compromised
by several biological liabilities including poor permeability
and absorption, rapid metabolism, high clearance, and low
oral availability. This has led to the emergence of the field
of peptidomimetics1 in which peptide-like activity is pre-
served while circumventing many of the aforementioned
liabilities through minimized rotational freedom, lower
molecular weight, and incorporation of features that enhance
selectivity and profit the biological profile.
incorporation, and relative stereochemical configuration
(Figure 1).
Recently, amino acid motifs constrained within a bicyclo-
[X,Y,0]lactam architecture have been applied to the design
of modified peptides and peptidomimetics in an effort to
discover new therapeutics and gain an improved understand-
ing of the interactions of ligands with target enzymes and
receptors.2-6 These compounds have displayed structural
variations with respect to ring size, degree of heteroatom
Figure 1. Constrained, bicyclic-lactam dipeptide scaffolds.
None of the syntheses for these scaffolds, however, have
enabled either the installation of angular, ring-junction sub-
stituents or endo heteroatom incorporation within both rings
(1) For recent reviews see: (a) Hruby, V. J. Nature ReV. Drug DiscoV.
2002, 1, 847. (b) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998,
2, 441. (c) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1244.
(2) For a recent review see: Hanessian, S.; McNaughton-Smith, G.;
Lombart H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
10.1021/ol030065h CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/19/2003

of the bicyclic system. These features were considered
worthy of investigation from both a synthetic and a biological
perspective in the discovery of new conformationally con-
strained, lactam-based amino acid scaffolds and peptidomi-
metics. Specifically, the introduction of these structural
elements would provide additional sites of diversification
enabling modulation for the probing of binding interactions
(i.e. hydrophobic and donor-acceptor interactions) not
possible in the structures of Figure 1. Furthermore, the
development of a flexible synthetic route that yields a
collection of lactam scaffolds bearing manipulatable func-
tional handles would facilitate diversification via combina-
torial methods, thus generating libraries of compounds based
on the bicyclic lactam core structure. We disclose herein an
efficient synthetic approach to oxazolo[3,2-a]pyrazin-5-ones,
a novel class of bicyclic lactam scaffolds for which ring-
junction substitution is accessed in a stereoselective fashion
and an amine functional handle is poised for exploitation in
rapid and diversity-oriented library synthesis.
This route would allow rapid, convergent incorporation of
diversity elements from both components of the cyclocon-
densation, and angular substitution would be installed at the
previously unexplored ring junction.
Our efforts were initiated by developing a reliable route
to the requisite 3-aza-1,5-ketoacids. We avoided a previously
reported route10 to these intermediates in favor of a novel,
more direct approach that began with alkylation of ethyl gly-
cinate with a variety of commercially available bromoaceto-
phenones (Table 1). Under the developed conditions, prod-
Table 1. Synthesis of N-Protected 3-Aza-1,5-ketoacids
It was quickly recognized that the cyclocondensation of
amino alcohols and ketoacids developed by Meyers7 could
in theory be applicable to analogous 3-aza-1,5-keto acids
(Scheme 1). Moreover, it was conceived that the rigid
Scheme 1. Retrosynthetic Analysis
ucts arising from dialkylation of ethyl glycinate were not
observed. This is presumably the result of an inductive
decrease in nucleophilicity of the product amine. Subsequent
Cbz protection of the crude mono N-alkylated glycine esters
under standard conditions followed by saponification fur-
nished the desired 3-aza-1,5-ketoacids 1a-e in 67-79% over
3 steps.
Anticipating strong acid lability of the bicyclic cyclocon-
densation products, the Cbz protecting group was chosen for
its easy removal under nonacidic conditions.11 In addition,
Cbz-protected substrates were predicted to be both stable
and soluble in the Meyers cyclocondensation conditions
(refluxing toluene).7
To achieve substituent diversity beyond arenes, the cor-
responding methyl-substituted aza ketoacid was also syn-
thesized. Optimal synthesis was achieved by alkylation of
N-Cbz ethyl glycinate with methallyl bromide to give ester
2 (Scheme 2). Oxidative cleavage of the olefin under
Johnson-Lemieux12 conditions provided methyl ketone 3,
which upon ester hydrolysis gave the target ketoacid 1f in
good overall yield.
stereocontrol observed in the formation of Meyers’ 5,5-
bicyclic8 lactams and specific 5,6 versions9 might be
preserved in the formation of our 5,6-aza bicyclic lactams.
(3) (a) Gu, X.; Tang, X.; Cowell, S.; Ying, J.; Hruby, V. J. Tetrahedron
Lett. 2002, 43, 6669. (b) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci,
M. D.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 145. (c) Estiarte, M. A.;
Rubiralta, M.; Diez, A.; Thormann, M.; Giralt, E. J. Org. Chem. 2000, 65,
6992.
(4) (a) Mizutani, N.; Chiou, W.-H.; Ojima, I. Org. Lett. 2002, 4, 4575.
(b) Sun, H.; Moeller, K. D. Org. Lett. 2002, 4, 1547.
(5) (a) Hanessian, S.; Buckle, R.; Bayrakdarian, M. J. Org. Chem. 2002,
67, 3387. (b) Wang, W.; Yang, J.; Ying, J.; Xiong, C.; Zhang, J.; Cai, C.;
Hruby, V. J. J. Org. Chem. 2002, 67, 6353. (c) Beal, L. M.; Liu, B.; Chu,
W.; Moeller, K. D. Tetrahedron, 2000, 56, 10113.
(6) (a) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N.; Moeller, K. D. J.
Org. Chem. 2000, 65, 2484. (b) Maison, W.; Kuntzer, D.; Grohs, D. Synth.
Lett. 2002, 11, 1795.
(7) For reviews see: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503. (b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843.
(8) In contrast to 5,5-bicyclic lactams, Meyers has reported that analogous
5,6-lactams bearing angular, alkyl substituents (R1 ) alkyl, Scheme 1) are
formed with diminished levels of diastereomeric control (see ref 7a).
(9) For recent precedence of complete diastereoselectivity in the formation
of an angular, phenyl-substituted Meyers 5,6-bicyclic lactam (R1 ) Ph,
Scheme 1) see: Amat, M.; Margalida, C.; Llor, N.; Bosch, J. Chem.
Commun. 2002, 526.
(10) Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.; Boger, D.
L. J. Am. Chem. Soc. 1996, 118, 2567.
(11) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999; pp 531-
537.
(12) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
2728
Org. Lett., Vol. 5, No. 15, 2003

phenylgylcinol, phenylalaninol, and serinol. This selection
enabled the degree of steric bulk to be varied and, in the
serinol case, an additional functional handle to be incorpo-
rated. Racemic mixtures of the amino alcohols were em-
ployed to provide access to both antipodes of final products
for biological testing. Attempts to use serine as the amino
alcohol component failed to produce the desired carboxyl
analogue (R2 ) CO2H) apparently due to poor solubility.
Carboxyl installation was eventually achieved through mild
oxidation of the serinol adducts (vide infra).
Scheme 2. Synthesis of Methyl-Substituted
3-Aza-1,5-ketoacid
For cyclization substrates bearing aryl substituents (entries
1-12), the bicyclocondensation was observed to occur with
complete syn diastereoselectivty in accord with the results
obtained in Meyers’ 5,5-bicyclic lactam systems8 and the
angular phenyl 5,6-lactam reported by Amat and Bosch.10
Assignment of the syn stereochemical orientation was based
on gradient NOESY experiments for which a strong NOE
interaction between the angular bridgehead and amino
alcohol substituents was found to be most diagnostic (Figure
2). In cyclizations involving methyl substrate 1f (entries
The pivotal bicyclocondensation was next explored. Grati-
fyingly, it was found that heating the prepared aza ketoacids
and 1,2-amino alcohols in toluene in the presence of catalytic
camphor sulfonic acid resulted in complete condensation-
bicyclization to furnish the desired Cbz-protected oxazolo-
[3,2-a]pyrazin-5-ones (Table 2). Water formed during the
Table 2. Results of Bicyclocondensation of
3-Aza-1,5-ketoacids
2-step
yield (%)a
entry
R1
Ph (1a )
Ph (1a )
Ph (1a )
R2
CH3
Ph
Bn
CH2OH
CH3
Ph
CH3
Bn
product
1
2
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
76
77
80
87b
78
83
83
74
Figure 2. Gradient NOESY results for 4g.
4
Ph (1a )
5
6
7
8
4-MeOPh (1d )
4-MeOPh (1d )
4-FPh (1b)
4-FPh (1b)
4-Cl (1c)
13-16), the reaction generally proceeded with high diaste-
reocontrol but formation of the minor diastereomer was
detected in levels as high as 11% (entry 14). The observed
syn diastereochemical outcome for the formation of the
oxazolo[3,2-a]pyrazin-5-ones may be adequately explained
via the mechanistic rationale applied to the 5,n Meyers
cyclodehydrations.13
The successful inclusion of serinol (entries 4 and 16) in
the bicyclocondensation was particularly interesting as it
introduced a point of diversification through O-functional-
ization. Along these lines, we found that the Cbz-protected
bicycles 4d and 4p could be readily O-alkylated, O-arylated,
and converted to carbamate derivatives thus increasing the
diversity of our scaffold collection.
9
Ph
65
10
11
12
13
14
15
16
4-PyPh (1e)
4-PyPh (1e)
4-PyPh (1e)
CH3 (1f)
CH3 (1f)
CH3 (1f)
CH3
Ph
Bn
CH3
Ph
Bn
4j
4k
4l
4m
4n
4o
4p
49
49
50
45c
72d
58e
55b,f
CH3 (1f)
CH2OH
a Isolated yield of pure, single diastereomer over two steps. b Yield of
Cbz intermediate. c 25/1.0 dr as determined by 400-MHz 1H NMR analysis.
d 8.3/1.0 dr as determined by 400-MHz H NMR analysis. e 9.1/1.0 dr as
1
determined by 400-MHz 1H NMR analysis. f 25/1.0 dr as determined by
1
400-MHz H NMR analysis.
Of greatest significance, the serinol-derived scaffolds 4d
and 4p could be transformed into constrained dipeptide
surrogates as follows. TEMPO-catalyzed oxidation of alco-
course of the reaction was removed azeotropically by aid of
a Dean-Stark apparatus. Liberation of the amine from Cbz
protection was smoothly carried out by hydrogenolysis
catalyzed by Pd on carbon providing bicyclic lactam scaf-
folds 4a-p in good yield over the two-step sequence.
Drawing from the commercial pool of 1,2-amino alcohols,
a select subset was chosen that was comprised of alaninol,
(13) (a) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem.
2001, 66, 1413. (b) Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994,
35, 2223. Unlike the more flexible 5,6 Meyers lactams described in the
above citations, an even greater degree of conformational rigidity is be-
lieved to reside within the Cbz-protected products 4a-p, thus strongly
disfavoring the formation of a highly strained and sterically compressed
anti product.
Org. Lett., Vol. 5, No. 15, 2003
2729

amines, using carbodiimide (method A) or mixed anhydride
activation (method B), and subsequent Cbz deprotection
furnished a diverse set of constrained modified dipeptides
7a-g in good yield (Table 3). Complete preservation of
stereochemical fidelity during the oxidation and subsequent
coupling was verified by NMR analysis in all cases.
In summary, we have developed an efficient and highly
stereoselective route to a new class of heterocyclic scaffolds
bearing the oxazolo[3,2-a]pyrazin-5-one core structure. The
key cyclocondensation of prepared 3-aza-1,5-ketoacids and
amino alcohols enabled single-step formation of both rings
with high diastereochemical control of angular substituents.
The efficient preparation of constrained dipeptide scaffolds
5 and 6 derived from serinol enables future investigation as
new bicyclic lactam-based peptidomimetics.
Scheme 3. Oxidation of Serinol-Derived Scaffolds
Table 3. Constrained, Modified Peptide Scaffolds via
Amidation
This synthetic approach is potentially applicable to other
suitably functionalized ketoacids (i.e. aspartic and glutamic
acid derivatives) to form additional classes of constrained
bicyclic peptide scaffolds in either racemic or enantio-en-
riched form. In addition, oxazolo[3,2-a]pyrazin-5-ones pre-
pared from enantio-pure amino alcohols could quite readily
serve as chiral templates for the preparation of stereo-defined,
substituted piperazines and piperazinones.
Acknowledgment. The authors thank Andrew Allen for
gradient NOESY NMR studies, Carolina Vong for analytical
support, and Nick Neitzel for sample preparation.
Supporting Information Available: General experimen-
tal procedures for the preparation of 1a-e, 1f, and 4a-p
1
and representative H NMR and gradient NOESY spectral
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL030065H
hols 4d and 4p under mild, buffered conditions14 proceeded
in excellent yield to provide the desired N-protected amino
acids 5 and 6 (Scheme 3). Coupling of these acids with
(14) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564.
2730
Org. Lett., Vol. 5, No. 15, 2003