First synthesis of BU-4664L

Article abstract of DOI:10.1016/j.tetlet.2015.08.070

The first synthesis of BU-4664L, an actinomycte-produced N-farnesylated dibenzodiazepinone with important biological activities, has been achieved in 18% overall yield from a known benzoic acid derivative by a nine-step sequence that involves an intramolecular Buchwald-Hartwig coupling of a sterically demanding bromo amine intermediate to install the unique tricyclic ring system.

Full text of DOI:10.1016/j.tetlet.2015.08.070

Accepted Manuscript
First synthesis of BU-4664L
Yusuke Takahashi, Takafumi Hirokawa, Mai Watanabe, Satomi Fujita, Yusuke
Ogura, Masaru Enomoto, Shigefumi Kuwahara
PII:
S0040-4039(15)30024-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.070
TETL 46654
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 July 2015
21 August 2015
25 August 2015
Please cite this article as: Takahashi, Y., Hirokawa, T., Watanabe, M., Fujita, S., Ogura, Y., Enomoto, M., Kuwahara,
S., First synthesis of BU-4664L, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.08.070
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First synthesis of BU-4664L
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Yusuke Takahashi, Takafumi Hirokawa*, Mai Watanabe,
Satomi Fujita, Yusuke Ogura, Masaru Enomoto, Shigefumi Kuwahara*

1
Tetrahedron Letters
First synthesis of BU-4664L
Yusuke Takahashi, Takafumi Hirokawa*, Mai Watanabe, Satomi Fujita, Yusuke Ogura, Masaru Enomoto,
and Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-
8555, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first synthesis of BU-4664L, an actinomycte-produced N-farnesylated dibenzodiazepinone
with important biological activities, has been achieved in 18% overall yield from a known
benzoic acid derivative by a nine-step sequence that involves an intramolecular Buchwald–
Hartwig coupling of a sterically demanding bromo amine intermediate to install the unique
tricyclic ring system.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
BU-4664L
Diazepinomicin
Alkaloid
Antitumor
Buchwald–Hartwig reaction
BU-4664L (1) was first discovered by Bristol-Myers Squibb
in the fermentation broth of the actinomycete Micromonospora
sp. M990-6 and shown to exhibit rat 5-lipoxygenase inhibitory
activity (IC50, 1.7 M), significant in vitro cytotoxicity against
several tumor cell lines (IC50, 1.1–18 M), and in vivo antitumor
activity against P388 leukemia and B16 melanoma (Figure 1).1
This compound was later reisolated from other Micromonospora
strains by some research groups2–6 and has also been referred to
analog synthesis, the synthesis of BU-4664L itself has never been
reported to date. We describe herein the first synthesis of 1,
which would endow SAR studies on 1 with more flexibility in
analog design.
as
ECO-04601
(or
ECO-4601),2,7
TLN-4601,8
or
diazepinomicin.3 Other important biological properties of 1 such
as antimicrobial activity,3 binding ability to peripheral
benzodiazepine receptor,9,10 anti-invasive and anti-angiogenic
activities,11 Ras-MAPK signaling pathway inhibitory effect,8,12
and antioxidant as well as anti-protease activities,5 have also been
reported so far. From a structural viewpoint, it is worth
mentioning that BU-4664L (1) is the only natural product that
incorporates a 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-
one core. The structural uniqueness of 1 as well as the intriguing
biological activities prompted its biosynthetic and structure–
activity relationship (SAR) studies,1,7,11,13–17 the latter of which
led to some promising analogs with better pharmacological
profiles.7,11 Most analogs employed in the SAR studies were
prepared by directly derivatizing 1 of natural origin,1,7,13,11 while,
for N-farnesylated dibenzodiazepinone analogs with simpler
substitution patterns on the benzene rings, intramolecular
condensation of amino carboxylic acid intermediates was utilized
for the formation of the tricyclic fused ring system.17 Despite the
appearance of a considerable number of SAR studies involving
Figure 1. Structure of BU-4664L (1).
Scheme 1 outlines our retrosynthetic analysis of BU-4664L
(1). We planed to install the seven-membered diazepinone ring in
1 by the intramolecular Buchwald–Hartwig coupling of 2; global
deprotection of the resulting tricyclic product would afford the
target molecule 1. The bromo amine intermediate 2 should
readily be prepared by reduction of nitro compound 3, which
would be obtainable by amide bond formation between benzoic
acid derivative 4 and protected 3,5-dihydroxyaniline 5.
———
 Corresponding authors. Tel./fax: +81 22 717 8783; e-mail: t.hirokawa@g-mail.tohoku-university.jp (T.H.), skuwahar@biochem.tohoku.ac.jp
(S.K.)

2
stage for the installation of the dibenzodiazepinone ring system
by the intramolecular Buchwald–Hartwig coupling. Despite our
concern that the steric congestion around both the amino group
and the bromine substituent of 13 might hamper the
intramolecular ring formation, treatment of 13 with Pd2(dba)3 (30
mol%) and P(o-tolyl)3 (60 mol%) in refluxing toluene in the
presence of t-BuONa afforded desired product 15, albeit in a
modest yield of 34%.20,21 Fortunately, this cyclization could be
improved significantly by using a catalyst system composed of
Pd2(dba)3, DavePhos (14) and t-BuONa;22,23 refluxing a mixture
of 13, Pd2(dba)3 (10 mol%), 14 (20 mol%), and t-BuONa in
toluene furnished 15 in an acceptable yield of 67%.24 Finally,
removal of the three TIPS groups with TBAF in 80% yield
Scheme 1. Retrosynthetic analysis of 1.
1
completed the synthesis of BU-4664L (1), the H and 13C NMR
spectra of which were identical with those of an authentic
material.4
In conclusion, the first synthesis of BU-4664L (1) was
achieved in 18% overall yield from the commercially available
benzoic acid derivative 6 by a 9-step sequence involving the
intramolecular Buchwald–Hartwig coupling of the highly
sterically demanding bromo amine 13 as the key step. The
successful completion of the synthesis of 1 would enable the
preparation of BU-4664L analogs with various side chains via N-
alkylation of intermediate 11, and thereby make it possible to
evaluate biological activities of thitherto unprepared analogs of 1
that possess an N-substituent other than sesquiterpenoidal fifteen-
carbon chains, such as a geranyl or a geranylgeranyl group, while
maintaining the substitution pattern on the two benzene ring of 1.
Acknowledgments
We are grateful to Prof. Igarashi (Toyama Prefectural
University) for providing NMR spectra of BU-4664L.
Supplementary data
Supplementary
data
(experimental
procedures,
characterization data, and copies of NMR spectra for new
compounds) associated with this article can be found, in the
online version, at doi:
References and notes
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Scheme 2. Synthesis of BU-4664L (1).
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Our synthesis of 1 began with the preparation of carboxylic
acid 8a (Scheme 2). Treatment of commercially available
hydroxy acid 6 with an excess amount of TIPSCl and imidazole
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farnesyl bromide to give 12 in 78% yield. The N-farnesylation of
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NH4Cl in aqueous EtOH gave 13 in 78% yield, which set the
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3
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