Ring opening of benzoxazinones: An improved and efficient synthesis of clavatustides A & B

Article abstract of DOI:10.1016/j.tetlet.2017.07.059

Ag₂O mediated esterification of (R)-tert-butyl 2-hydroxy-3-phenylpropanoate has been realized via the effective ring opening of benzoxazinones that resulted in the efficient synthesis of cyclodepsipeptides clavatustides A and B and their enanti

Full text of DOI:10.1016/j.tetlet.2017.07.059

Accepted Manuscript
Ring Opening of Benzoxainones: An Improved and Efficient Synthesis of Clav-
atustides A & B
Suresh Kumar Chettu, Lakshmi Narayana Sharma Konidena, Korupolu Raghu
Babu, N.S. Kameswara Rao, Raju Doddipalla, Hima Bindu Gandham,
Ramakrishna Guduru
PII:
S0040-4039(17)30914-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.059
TETL 49141
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 June 2017
11 July 2017
16 July 2017
Please cite this article as: Chettu, S.K., Konidena, L.N.S., Babu, K.R., Kameswara Rao, N.S., Doddipalla, R.,
Gandham, H.B., Guduru, R., Ring Opening of Benzoxainones: An Improved and Efficient Synthesis of Clavatustides
A & B, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.059
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Ring Opening of Benzoxainones: An
Improved and Efficient Synthesis of
Clavatustides A & B
Leave this area blank for abstract info.
Suresh Kumar Chettua,b, Lakshmi Narayana Sharma Konidenaa,b, Korupolu Raghu Babub, N.
S.Kameswara Raoa, Raju Dudppaa, Hima Bindu Gandham b and Ramakrishna Gudurua*
O
R
N
OtBu
O
O
O
R
HN
(S)
O (S)
O
TFA, CH2Cl2
0 °C to rt, 12h
tBuO
N
O
OH
7
T3P, DIPEA, THF
0 °C to rt, 12h
NH
NH HN
O
Ag2
O
O
THF, rt, 48 h
O
OtBu
O
(S)
O
O
N
R = Et (8a) 85%
R = Me (8b) 86%
R = Et (S)-Clavastutide A 35%
R = Me (S)-Clavastutide B 34%
O
O
R
N
NH
R
N
OtBu
O
CH3
CH3
O
O
4
O
O
CH3
(R)
O
HN
O
TFA, CH2Cl2
0 °C to rt, 12h
R
N
R = Et (4a)
R = Me (4b)
O
T3P, DIPEA, THF
0 °C to rt, 12h
NH HN
O
NH
O
O
THF, rt, 48 h
Ag2
O
OtBu
(R)
O
O
O
(R)
tBuO
OH
R = Et (R)-Clavastutide A 32%
R = Me (R)-Clavastutide B 33%
R = Et (ent 8a)
84 %
8b)
85%
7-ent
R = Me (
ent

1
Tetrahedron Letters
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Ring Opening of Benzoxainones: An Improved and Efficient Synthesis of
Clavatustides A & B
Suresh Kumar Chettua,b, Lakshmi Narayana Sharma Konidenaa,b, Korupolu Raghu Babub, N. S.Kameswara
Raoa, Raju Doddipallaa, Hima Bindu Gandham b and Ramakrishna Guduruc*
a GVK Biosciences Private Limited, Medicinal Chemistry Laboratory, Hyderabad 500076, India
b Andhra University, Department of Engineering Chemistry, Andhra University College of Engineering (A), Visakhapatnam 530003, India.
cPiramal Pharma Solutions, Ahmedabad, 382213, India
ARTICLE INFO
ABSTRACT
Article history:
Received
2009 Elsevier Ltd. All rights reserved.
Received in revised form
Accepted
Ag2O mediated esterification of (R)-tert-butyl 2-hydroxy-3-phenylpropanoate has been realized
via the effective ring opening of benzoxazinones that resulted in the efficient synthesis of
cyclodepsipeptides clavutustides A and B and their enantiomers in very good overall yields
Available online
Keywords:
Clavatustide A & B
Ring opening
Benzoxazinones
Cyclodepsipetides
Anticancer
1. Introduction
associated molecules including cyclin E2 played key roles in the
clavatustide B-induced cell cycle blocking.
Cyclodepsipeptides with a broad spectrum of biological
activities including anti-plasmodial, antiviral, insecticidal,
cytotoxic and anti-proliferative activities1 also serve as lead
compounds/templates for more pharmacologically potent and
toxicologically safe derivatives.2 With the latest advancements in
the structural and pharmacological characterization of naturally
occurring cyclic peptides and depsipeptides,3 these compounds
plays an important role in the development of novel therapeutics.
While cyclic peptides with unique biological activities are
ubiquitous in nature,4 anthranilic acid unit are rare in nature and
anthranilic acid dimers with micromolar affinity for the CCK1
receptors were considered to be an important molecular scaffold
in medicinal chemistry5 Cyclodepsipeptides clavatustides A and
B (Figure 1) containing an anthranilic acid dimer and D-
phenyllactic acid are such molecules that were isolated by Bin
Wu and co-workers from cultured mycelia and broth of
Aspergillus clavatus C2WU isolated from Xenograpsus
testudinatus.6 Clavatustide B, the product isolated from clavatus
C2WU, exhibited a potent anti-cancer activity in various human
cancer cell lines, including liver, pancreatic, gastric, colorectal,
and prostate cancers and retinoblastoma.6 Clavatustide B is a
promising anti-cancer agent against chemo- and radio-therapy
resistant cancers6a as it has shown a potent inhibition of cell
growth in chemo- and radio therapy resistant cell lines,
pancreatic cancer cell line (panc-1)6b and prostate cancer cell line
(PC3)6c. Its anti-cancer property is due to the delaying of G1-S
phase cell cycle transition7. The G1-S cell cycle checkpoint-
Figure 1. Clavatustides A & B
One of the challenges associated with the synthesis of
depsipeptides is the limited availability of coupling reagents for
the ester formation using α-hydroxyacid/esters.8 It has been
reported in the literature that benzoxazinones undergo
nucelophilic ring opening with alcohols and amines and are
intermediates for the synthesis of various molecules such as
benzoxazinethiones,
benzothiazinethiones,
substituted
amidobenzoates, 4-hydorxyquinolinones and quinazolinones.9
This prompted us to explore the possibility of ring opening of
benzoxazinone for the formation of the ester as an alternative
method for the synthesis of clavatustides A and B. We have
recently reported the first total synthesis of clavatustides A and B
and its analogues that has established the correct values of optical
rotation for these compounds in pure form.10
In continuation of our efforts towards the improved synthesis of
clavatustides A and B, here in we report the ring opening of

2
Tetrahedron Letters
benzoxazinone as an alternate route for the efficient synthesis
of clavatustides A and B and its analogues.
of ester by LCMS in 10 and 15% respectively, conditions shown
in entries 3 and 4 (pyridine/DMF) did not indicate any product
formation
Scheme 2. Synthesis of compounds 4a & 4b:
Scheme 3: Synthesis of Compound 8b:
Sr.No conditionsa
yieldb
Scheme 1
1
2
3
4
5
DBU/DMF/0 °C
10%
Retrosynthesis
NaH/DMF/0 °C
Pyridine/DMF/120 °C
Pyridine/rt
15%
Retro synthetically, macro lactamization was our preferred
mode of cyclization. From the disconnection of ester
functionality of 4 (scheme 1) it was envisioned that the
nucleophilic ring opening of benzaxazinone 6 with methyl
phenyllactate 5 would provide us the key compound 4 that would
be set up for macro lactamizaton. Further disconnection of 6 gave
rise to benzoxazinone 2 and N-alkyl glycine derivatives. The
forward synthesis commenced with the synthesis of
benzoxazinone 2 in 70% yields as per the reference protocol.11
The benzoxazinone 2 was then coupled using the standard amide
formation using DCC in CH2Cl2 with N-Boc-N-methylglycine 3a
to afford 4a in 60 % yields while N-Boc-N-ethylglycine 3b
afforded 4b in 63% yields (Scheme-2).
No product
No product
82%c
Ag2O/THF
a
Table 1: reactions were run on 4b (1 mmol), 7 (1 mmol);
conversion based on LCMS; c isolated yield
b
Gratifyingly, using the conditions optimized for the ring
opening of benzoxazinones, treatment of 4a and 4b with (S)-tert-
butyl 2-hydroxy-3-phenylpropanoate (scheme-4) in the presence
of Ag2O in THF resulted in the clean conversion to 8a and 8b as
a single isomer. Compounds 8a and 8b were isolated in 85% and
86% respectively. Similarly, treatment of benzoxazinones 4a and
4b with (R)-tert-butyl 2-hydroxy-3-phenylpropanoate afforded
ent-8a and ent-8b as single isomers in 84% and 85%
respectively. Compounds 8a, 8b were then subjected to boc-
deprotection using TFA and the obtained crude product was
treated with T3P to obtain S-clavatustides A and B in 35 % and
34 % respectively. Similarly, Compounds ent-8a and ent-8b were
subjected to boc-deprotection followed by treatment with T3P to
obtain R-clavatustides A and B in 32% and 33% respectively.
Thus, the direct ring opening of benzoxazinones allowed us to
synthesize clavatustides A and B in an overall yield of 12.5% and
12.9% respectively which is an improvement over the previously
reported 9.1 % overall yield for the same.
With compounds 4a and 4b in hand, we turned our attention to
the ring opening of benzoxazinones with (S)-tert-butyl 2-
hydroxy-3-phenylpropanoate (Scheme 3). A potential issue
considered during the ring opening was the racemization of the
phenyl lactate under the reaction conditions. Table-1 illustrates
the optimization table for the esterification of α-hydroxyesters via
ring opening of benzoxazinones. A short screen for the optimal
conditions revealed that benzoxazinone 4a could be opened with
(S)-tert-butyl 2-hydroxy-3-phenylpropanoate in the presence of
Ag2O in THF to afford the desired ester 8a as a single isomer in
82% isolated yield. While conditions shown in entries 1 and 2
(DBU/DMF/0 ⁰C and NaH/DMF/0 °C) indicated the formation

3
O
R
N
OtBu
O
O
tBuO
O
R
HN
O
TFA, CH2Cl2
0 °C to rt, 12h
OH
(S)
N
7
O
O
Ag2O
THF, rt, 48 h
(S)
T3P, DIPEA, THF
0 °C to rt, 12h
NH
NH HN
O
O
O
OtBu
O
(S)
O
O
N
R = Et (S)-Clavastutide A
R = Me (S)-Clavastutide B
35%
34%
R = Et (8a)
R = Me (8b)
85%
86%
O
O
NH
R
N
R
N
OtBu
O
CH3
CH3
O
O
O
O
CH3
O
(R)
O
HN
4
tBuO
R
R = Et (4a)
R = Me (4b)
TFA, CH2Cl2
0 °C to rt, 12h
N
O
OH
Ag2(OR)
O
7-
ent
NH HN
O
NH
T3P, DIPEA, THF
0 °C to rt, 12h
THF, rt, 48 h
O
O
O
OtBu
(R)
O
R = Et (R)-Clavastutide A
R = Me (R)-Clavastutide B
32%
33%
R = Et (
ent
R = Me (ent 8b)
8a)
84 %
85%
Scheme 4: Total synthesis of (S)-Clavastutide A & (R)-Clavastutide A:
15, 40-56 and references cited therein (j) G. M. S. Jimenez, A. B.
Hernandez and J. M. E. Brauer, Marine Drugs 2012, 10, 963-986
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Shan, W. Xiaodan, G. Lishe, Y. Ying and W. Bin, Marine Drugs,
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An effective and an alternative method for the esterification of
α-hydroxyesters in the synthesis of depsipeptides have been
identified and its utility was demonstrated by the synthesis of
clavatustides A & B. A short and efficient synthesis of
clavatustides A and B was achieved in 4 steps with an overall
yield 12.5 and 12.9 respectively.
Acknowledgments
The authors express their profound thanks to the management
of GVK Biosciences Private Limited for financial support. The
encouragement rendered by Dr. Sudhir Kumar Singh throughout
this work is deeply acknowledged. Our sincere gratitude to Dr.
K. Muralidharan, Mr. Vijay Bomaluri for analytical support.
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Supplementary Material
Supplementary data and experimental procedures
(Spectroscopic data for compounds clavatustides A and B
associated with this article can be found, in the online
version.
Click here to remove instruction text...

4
Tetrahedron
Highlights:
1. An alternative method for the esterification
of α-hydroxyesters has been developed.
2. Ring opening of benzoxazinones with α-
hydroxy esters was demonstrated
3. Synthesis of clavatustides A and B was
achieved in 4 steps with good overall yield
4. Both enantiomers or clavatustides A and B
synthesized using the newly developed
method