Novel methodologies for the synthesis of functionalized pyroglutamates

Article abstract of DOI:10.1039/c0cc05609j

Alkylation of amino-acid derived iminoesters with Baylis-Hillman (BH) template based allyl bromides furnished α-methylene-β-substituted- pyroglutamates, while the corresponding alkylation with BH derived allylic acetates provided α-alkylidene-pyroglutamates. These methodologies have been applied in the synthesis of fused [3.2.0]-γ-lactam-β-lactones.

Full text of DOI:10.1039/c0cc05609j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 3219–3221
www.rsc.org/chemcomm
COMMUNICATION
Novel methodologies for the synthesis of functionalized pyroglutamateswz
Srinivas Tekkam,a M. A. Alam,a Subash C. Jonnalagaddab and Venkatram R. Mereddy*a
Received 16th December 2010, Accepted 26th January 2011
DOI: 10.1039/c0cc05609j
Alkylation of amino-acid derived iminoesters with Baylis–Hillman
(BH) template based allyl bromides furnished a-methylene-
b-substituted-pyroglutamates, while the corresponding alkylation with
BH derived allylic acetates provided a-alkylidene-pyroglutamates.
These methodologies have been applied in the synthesis of fused
[3.2.0]-c-lactam-b-lactones.
properties.2,3 Owing to the importance of the pyroglutamate
template in many areas, there have been several reports in the
literature towards the synthesis and applications of these
valuable heterocycles.1–4 However, the development of simple,
highly tunable methodologies for the diverse functionalization
of the pyroglutamate ring are still required to expand the
scope and utility of these scaffolds.
Baylis–Hillman (BH) reaction is a very important C–C bond
forming reaction in organic synthesis that provides densely
functionalized allylic alcohols in a single step.5 The bromides 8
or acetates 9 derived from BH alcohols can undergo nucleo-
philic allylic rearrangement to furnish a wide variety of
trisubstituted olefins.5 Amino acids are inexpensive starting
materials and the imines derived from the amino esters have
been utilized as valuable synthons in alkylation chemistry for
the synthesis of unnatural amino acids.4,6
Five membered azaheterocyclic structural units such as
pyroglutamates (g-carboxy-g-lactams) and their derivatives
are prevalent scaffolds that serve as important building blocks
for the syntheses of numerous nitrogen containing natural
products and heterocycles.1 Functionalization of the carboxylate
group and the lactam ring in pyroglutamates allows the
preparation of many types of structurally complex molecules.1
Pyroglutamate derived fused or spiro-heterobicyclic compounds
also hold a prominent position in natural products chemistry
(Fig. 1).2 For example, lactacystin 1, and cinnabaramide (4)
are secondary metabolites derived from terrestrial strain
of Streptomyces sp. and salinosporamides 2 are natural
products produced by marine actinomycete Salinispora tropica.2
Similarly, spiro-bicyclic b-lactone-g-lactam subunit bearing
natural products such as oxazolomycins, lajollamycin, etc.
were isolated from different strains of Streptomyces sp.3
All these compounds have been found to exhibit potent
anti-cancer, anti-microbial, and other important medicinal
We envisioned that the alkylation of the imino esters with
Baylis–Hillman reaction derived allylic bromides or acetates
should provide functionalized pyroglutamates upon acidic
work up. We chose three amino acids valine, leucine, and
phenylalanine as representative examples for the current
study. We initiated the synthesis with esterification of these
amino acids as benzyl esters 5a–c. Imines 7a–c were obtained
via condensation of aminoesters 5 with p-chlorobenzaldehyde
6 and they were utilized without further purification in the
synthesis of pyroglutamates. The requisite allyl bromides 8a–c
were prepared in two steps via the BH reaction of the
corresponding aldehydes with methyl acrylate followed by
bromination of the resulting alcohols.5 Reaction of iminoesters
7a–c with LHMDS in THF at 0 1C for one hour generated the
corresponding iminoenolates. Alkylation of these enolates
with BH bromides 8a–c provided the pyroglutamates 10a–i
upon proteolytic cleavage followed by lactamization in refluxing
toluene (Table 1). The reaction with bromides 8b and 8c was
found to be highly selective and in all the cases studied, the
b-substituted pyroglutamates (10b–c, 10e–f, 10h–i) were
obtained as single diastereomers after column chromato-
graphy (Table 1). The relative stereochemistry was confirmed
using single crystal X-ray crystallography of the valine derived
b-methyl substituted pyroglutamate 10b and phenylalanine
derived b-phenyl substituted pyroglutamate 10f.
Fig. 1 Pyroglutamate based natural products.
a Department of Chemistry and Biochemistry, University of Minnesota
Duluth, 1039 University Drive, Duluth, MN 55812, USA.
E-mail: vmereddy@d.umn.edu; Fax: +1-218-726-7394;
Tel: +1-218-726-6766
b Department of Chemistry and Biochemistry, Rowan University,
201 Mullica Hill Road, Glassboro, NJ 08028, USA.
E-mail: jonnalagadda@rowan.edu; Fax: +1-856-256-4478;
Tel: +1-856-256-5452
To demonstrate the robustness of this protocol, several of
these pyroglutamates were obtained routinely in multiple gram
quantities with utmost ease. Although the mechanistic details
have not been studied, we presume that the reaction proceeds via
Michael addition of a-iminoenolate 12 to BH bromide 8a–c and
w Dedicated to Professor Yashwant D. Vankar (Indian Institute of
Technology, Kanpur, India) on the occasion of his 60th Birthday.
z Electronic supplementary information (ESI) available: Experimental
and spectral data along with 1H and 13C NMR, Mass and X-Ray Spectra
are available. CCDC 805099–805101. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c0cc05609j
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3219–3221 3219

View Article Online
Table 1 Preparation of a-methylene-b-substituted-g-lactams
#
1
Imine
Bromide
Lactam
Ylda
67%
2
3
7a
7a
58%
66%
Scheme 1 Plausible mechanism for the observed diastereoselectivity.
7a with LHMDS followed by reaction of the resulting enolate
with BH acetates 9a–b and subsequent acidic work afforded
the a-alkylidene pyroglutamates 11a–b (Table 2). The pyro-
glutamates 11c–f were obtained starting with leucine and
phenylalanine iminoesters 7b–c respectively (Table 2). While
compounds 11b, 11d, and 11f derived from benzaldehyde BH
acetate 9b were obtained essentially as single diastereomers,
the corresponding compounds 11a, 11c and 11e derived from
acetaldehyde BH acetate 9a were obtained in B9 : 1 diastereo-
meric ratio favoring the E diastereomer. All these compounds
could be readily purified by silica gel column chromatography
to afford diastereomerically pure E-pyroglutamates 11a–f.
We then applied the above methodologies for the synthesis
of fused bicyclic lactones such as [3.2.0]-g-lactam-b-lactones.
These types of moieties are found in several natural products
such as those shown in Fig. 1. We envisaged the pyroglutamates
10 synthesized in the protocols mentioned above would act as
excellent precursors for the synthesis of the fused bicyclic
molecules. We initiated the synthesis of fused [3.2.0]-g-lactam-
b-lactones with the isomerization of the exocyclic methylene
group in lactams 10a, 10d, 10g with RhCl37 in refluxing THF to
provide the thermodynamically stable internal alkenes 16a–c in
quantitative yield. Substrate controlled dihydroxylation with
OsO4 and NMO afforded diol lactams 17a–c as the major
diastereomers. In the case of valine lactam (17a) the dr was
observed to be 415: 1, while for leucine and phenylalanine
lactams 17b–c the dr was found to be B10 : 1 upon silica
gel column chromatography. The diol lactams 17a–c were
subjected to regioselective deoxygenation under Barton–
McCombie8 conditions to provide the b-hydroxy-g-lactams
19a–c in good yield. The diols upon esterification with
diimidazolyl thiocarbonyl in refluxing THF provided the
thiocarbonate esters 18a–c in 85–90% yield. Deoxygenation
of the carbonate ester with Bu3SnH and AIBN in refluxing
benzene did not provide high selectivity and both isomers were
obtained in 1 : 1 ratio. We then employed the deoxygenation at
low temperatures (ꢀ78 1C) using triethylborane/O2 as the
radical source.9 Fortunately, these conditions improved the
diastereoselectivity to provide b-hydroxy-g-lactams 19a–c. In
the case of valine lactam (19a) the dr was observed to be
B10 : 1, while for leucine and phenylalanine lactams 19b–c the
dr was found to be B5 : 1 upon silica gel column chromatography.
4
5
6
60%
7b
7b
53%
57%
58%
7
8
7c
7c
51%
56%
9
a
Isolated overall yield starting from iminoesters 7a–c via a three-step
(alkylation/imine-deprotection/lactamization) protocol.
concomitant elimination of allylic bromide to furnish the imine
15, which upon acidic workup furnishes the pyroglutamate 10a–i.
The observed diastereoselectivity could probably be explained
based on the selective Michael addition from the sterically less
hindered face (transition states 13A and 13B, Scheme 1).
Similarly, a-alkylidine-g-carboxy-g-lactams 11a–f were
synthesized via the alkylation of iminoesters 7a–c with BH
reaction derived acetates 9a–b. Treatment of valine iminoester
c
3220 Chem. Commun., 2011, 47, 3219–3221
This journal is The Royal Society of Chemistry 2011

View Article Online
Table 2 Preparation of a-alkylidene-g-carboxy-g-lactams
provided a-alkylidene-g-carboxy-g-lactams in good yields.
The two procedures mentioned above are complimentary to
each other and a multitude of functionalized pyroglutamates
can be efficiently synthesized in multi gram quantities. These
methodologies were applied in the short synthesis of fused
bicyclic molecules such as g-lactam-b-lactones. The current
protocols should facilitate the ready synthesis of a wide range
of functionalized pyroglutamate analogs owing to the flexibility
of BH reaction and the availability of a variety of natural/
unnatural amino acids.
#
1
Imine
Bromide
Lactam
Ylda
62%
We thank University of Minnesota Academic Health Center
Faculty Development Grant (VRM), Whiteside Institute for
Clinical Research Grant (VRM), and Rowan University
Financial Support Grant (SCJ) for partial support of the
project. We thank Dr Victor G. Young, Jr. (University of
Minnesota X-ray Crystallographic Laboratory) for providing
the crystal structures.
2
‘‘
68%
3
4
5
57%
64%
Notes and references
1 (a) S. K. Panday, J. Prasad and D. K. Dikshit, Tetrahedron: Asymmetry,
2009, 20, 1581–1632; (b) C. Najera and M. Yu, Tetrahedron: Asymmetry,
1999, 10, 2245–2303; (c) M. B. Smith, Alkaloids: Chem. Biol. Perspect.,
1998, 12, 229–287; (d) R. Benoit, C. Pascal, F. Dominique and
S. Francois, Trends Heterocycl. Chem., 1991, 2, 155–204.
2 (a) T. A. M. Guilder and B. S. Moore, Angew. Chem., Int. Ed., 2010,
49, 9346–9367; (b) M. Shibasaki, M. Kanai and N. Fukuda,
Chem.–Asian J., 2007, 2, 20–38; (c) M. Stadler, J. Bitzer,
A. M. Bartschmid, H. Muller, J. B. Buchholz, F. Gantner,
H. V. Tichy, P. Reinemer and K. B. Bacon, J. Nat. Prod., 2007,
70, 246–252; (d) C. E. Masse, A. J. Morgan, J. Adams and
J. S. Panek, Eur. J. Org. Chem., 2000, 2513–2528.
3 (a) O. Onyango, J. Tsurumoto, N. Imai, K. Takahashi, J. Ishihara
and S. Hatakeyama, Angew. Chem., Int. Ed., 2007, 46, 6703–6705;
(b) P. G. Bulger, M. G. Moloney and P. C. Trippier, Org. Biomol.
Chem., 2003, 1, 3726–3737; (c) W. Zhaoyang and M. G. Moloney,
Tetrahedron Lett., 2002, 43, 9629–9632; (d) P. N. Julien, Papillon
and R. J. K. Taylor, Org. Lett., 2000, 2, 1987–1990.
4 (a) A. Bertoli, L. Fanfoni, F. Felluga, G. Pitacco and E. Valentin,
Tetrahedron: Asymmetry, 2009, 20, 2305–2310; (b) T. Yamada,
K. Sakaguchi, T. Shinada, Y. Ohfune and V. A. Soloshonok, Tetra-
hedron: Asymmetry, 2008, 19, 2789–2795; (c) S. Kobayashi, T. Tsubogo,
S. Saito and Y. Yamashita, Org. Lett., 2008, 10, 807–809;
(d) P. V. Ramachandran, S. Madhi, L. B. Berry, M. V. R. Reddy
and M. J. O’Donnell, J. Am. Chem. Soc., 2005, 127, 13450–13451.
5 D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010,
110, 5447–5674.
6 (a) T. Kano, T. Kumano and K. Maruoka, Org. Lett., 2009, 11,
2023–2025; (b) C.-G. Chen, X.-L. Hou and L. Pu, Org. Lett., 2009,
11, 2073–2075; (c) T. B. Poulsen, G. Dickmeiss, J. Overgaard and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2008, 47, 4687–4690;
(d) C. Schmidt and U. Kazmaier, Org. Biomol. Chem., 2008, 6,
4643–4648; (e) M. J. Buller, C. B. Gilley, B. Nguyen, L. Olshansky,
B. Fraga and Y. Kobayashi, Synlett, 2008, 2244–2248;
(f) C. B. Gilley, M. J. Buller and Y. Kobayashi, Synlett, 2008,
2249–2252; (g) T. Hashimoto and K. Maruoka, Chem. Rev., 2007,
107, 5656–5682; (h) F. Z. Zradni, J. Hamelin and A. Derdours,
Molecules, 2007, 12, 439–454; (i) S. Arai, F. Takahashi, R. Tsuji and
A. Nishida, Heterocycles, 2006, 67, 495–501; (j) M. J. O’Donnell,
Acc. Chem. Res., 2004, 37, 506–517; (k) B. Lygo and B. I. Andrews,
Acc. Chem. Res., 2004, 37, 518–525; (l) P. P. Sun, M. Y. Chang,
M. Y. Chiang and N. C. Chang, Org. Lett., 2003, 5, 1761–1763;
(m) L. N. Goswami, S. Srivastava, S. K. Panday and D. K. Diskhit,
Tetrahedron Lett., 2001, 42, 7891–7892.
‘‘
55%
63%
6
‘‘
a
Isolated overall yield starting from iminoesters 7a–c via a three-step
(alkylation/imine-deprotection/lactamization) protocol.
Further debenzylation with Pd–C furnished hydroxy acids
20a–c that upon BOPCl treatment provided the requisite
[3.2.0] g-lactam-b-lactones 21a–c (Scheme 2). All these
compounds were characterized via proton, carbon NMR,
HRMS and single crystal X-ray analysis of compound 21b.
In conclusion, we have developed a novel and exceptionally
short methodology for the synthesis of a-methylene-b-
substituted-g-carboxy-g-lactams via alkylation of amino acid
derived iminoesters with BH reaction derived allyl bromides.
Similarly, alkylation of iminoesters with BH allyl acetates
7 J. Andrieux, D. H. R. Barton and H. Patin, J. Chem. Soc., Perkin
Trans. 1, 1977, 359–363.
8 (a) D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin
Trans. 1, 1975, 1574–1585; (b) D. Crich and L. Quintero, Chem.
Rev., 1989, 89, 1413–1432.
Scheme 2 Synthesis of fused [3.2.0] g-lactam-b-lactones.
9 C. Ollivier and P. Renaud, Chem. Rev., 2001, 101, 3415–3434.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3219–3221 3221