Synthesis of complete carbon framework of baulamycin A

Article abstract of DOI:10.1016/j.tetlet.2017.06.011

The total carbon framework with all chiral carbons of proposed structure of baulamycin A is synthesized using Evans’ aldol and Grubbs’ cross-metathesis as key reactions. This strategy enables one to access all the isomers of this natural product.

Full text of DOI:10.1016/j.tetlet.2017.06.011

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of complete carbon framework of baulamycin A
Srinu Paladugu a,c, Prathama S. Mainkar b,c, Srivari Chandrasekhar a,c,
⇑
a Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Acadamy of Scientific and Innovative Research, New Delhi 110025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The total carbon framework with all chiral carbons of proposed structure of baulamycin A is synthesized
using Evans’ aldol and Grubbs’ cross-metathesis as key reactions. This strategy enables one to access all
the isomers of this natural product.
Received 11 April 2017
Revised 2 June 2017
Accepted 3 June 2017
Available online xxxx
Ó 2017 Published by Elsevier Ltd.
Keywords:
Baulamycin
Aldol reaction
Cross-metathesis
Total synthesis
The burgeoning research to identify chemicals from nature with
potential antibiotic properties has led to many drugs and leads.1
However rapid resistance developed by the pathogens is alarming.
The low levels of interest in this area by pharmaceutical industries
need to be balanced by aggressive approach from academic envi-
ronment. While pharmaceutical industry has focussed its resources
in enhancing the activity of existing pharmacophores, the aca-
demic institutions have embarked on identifying new mechanistic
pathways to control the pathogen growth. Some such studies
revealed that both Gram-positive and Gram-negative bacteria
acquire iron utilizing virulence associated siderophores which are
essential for bacterial survival.2 The biosynthetic enzyme of sidero-
phores has been targeted with small membered molecules to gen-
erate leads in antibiotics drug discovery.3 (Fig. 1).
seven asymmetric carbons including three hydroxyl groups, three
methyl groups and one isobutyl group, dihydroxy phenyl ring
and ethyl or methyl ketone at the end. The anti-bacterial properties
of baulamycin A (1a) especially towards SbnE and AsbA prompted
us to take up the total synthesis of this natural product. Disap-
pointingly, while the work was at fag end, Goswami et al. reported
the total synthesis of proposed structure of baulamycin A and two
other isomers whose data did not match with the reported data.5
While both syntheses of ours and Goswami et al. relied on Evans’
chemistry, we employed Grubbs’ metathesis (vide supra), whereas
Goswami et al. used Wittig olefination to build the framework.
Herein we report a strategy which allows installation of all carbon
frame work with flexibility to stereodivergence.
The retrosynthetic scheme was designed with a purpose, that
will enable one to introduce structural and strereochemical diver-
sity with minimal synthetic interventions. Extensive asymmetric
Recently, baulamycins A (1a) and B (1b) were isolated from
Streptomyces tempisquensis and structures were established using
extensive chromatographic techniques.4 While baulamycin
A
and substrate controlled aldol reactions (for C4-C5, C12-C13, C1 -
0
exhibited in vitro bioactivities against NIS (nonribosomal peptide
C14) and stereoselective reduction (C11) were utilised to install all
synthetase independent siderophore) and SbnE (synthetase sidero-
stereocentres whereas C9-C10 stitching was achieved through
Grubbs’ cross-metathesis reaction. The two key fragments envis-
aged are aryl unit 3 embedded with four chiral carbons (styrene
unit to support cross metathesis as a type-II olefin to avoid any
anticipated self-metathesis) and lipophilic methyl rich olefin unit
4. The aryl unit 3 in turn was conceived from Evans’ aldol reaction
between aldehyde 6 and amide 7 and Mukaiyama aldol reaction
with silyl enol ether 5. Similarly, the liphophic intermediate 4
can be obtained from commercially available Roche ester 8 via
Evans methylation and aldol reaction with 3-pentanone (Fig. 2).
phore staphylo bath biosynthesis protein) at IC50 4.8
lM, baulamy-
cin B exhibited IC50 19 M. Both compounds showed good activity
l
against NIS synthetase Bacillus anthracis siderophore biosynthesis
protein of (AsbA) also. The baulamycins A and B differ by only
one methyl group at the terminus. The structural features contains
⇑
Corresponding author at: Division of Natural Products Chemistry, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007, India.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
http://dx.doi.org/10.1016/j.tetlet.2017.06.011
0040-4039/Ó 2017 Published by Elsevier Ltd.
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S. Paladugu et al. / Tetrahedron Letters xxx (2017) xxx–xxx
The (R)-Roche’s ester was converted to 14 following literature
procedure.9 Reduction of ,b-unsaturated ester10 14 using NiCl2/
a
NaBH4 furnished silyl ether 15 with excellent yield. Hydrolysis
of ester 15 to acid 16 followed by coupling with chiral auxiliary
17 under PivCl/Et3N conditions provided Evans amide 18 which
on alkylation with LiHMDS and MeI at ꢀ78 °C provided 19 in
92% yield with excellent diastereoselectivity.11 The reductive
cleavage of auxiliary in 19 with LiBH4 furnished alcohol 20 in
83% yield. Oxidation of alcohol 20 followed by reaction with the
TiIV enolate of pentan-3-one afforded two aldol products 21a
(72%) and 21b (15%).12 Both isomers were separated by simple
column chromatography and major isomer was assigned as anti-
Felkin product 21a based on literature precedence (Scheme 2).13
Deoxygenation of the secondary alcohol 21a using two-step
Barton-McCombie protocol14 furnished ketone 22 in 76% yield
which on subsequent desilylation gave alcohol 23 in good
yield. Homologation with methylene group was achieved via
oxidation of alcohol to aldehyde followed by Wittig olefination
with methyltriphenylphosphonium bromide and n-BuLi base in
decent yield to furnish the second cross-metathesis partner 4
(Scheme 3).
The stitching of two olefin partners 3 and 4 was achieved using
Grubbs’ 2nd generation catalyst without any self-dimerization to
achieve 23 in 54% yield (Scheme 4).15
Conversion of 2 to Baulamycin A (1a) is expressed to occur
via deprotection of the protecting groups. At this point, the pub-
lication by Goswami et al. appeared in print which has reported
that the structure assigned to baulamycin A (1a) did not match
with the synthetic compound. As we have also targeted the
proposed structure the synthetic efforts were terminated at this
stage.
Fig. 1. Proposed structure of baulamycin A & B.
Thus, commercially available dimethoxybenzaldehyde 6 and
oxazolidinone 7 under the influence of TiCl4, NMP and DIPEA in
CH2Cl2 at 0 °C furnished compound 9 in 68% yield with excellent
stereocontrol.6 The resulting sec-alcohol functionality in 9 was pro-
tected as silyl ether 10 with TBSOTf and 2,6-lutidine in CH2Cl2 in
88% yield. Reductive removal of Evans auxiliary was accomplished
with LiBH4 in EtOH to generate alcohol 11 in 90% yield. Swern oxi-
dation of alcohol 11 yielded aldehyde which underwent a smooth
Mukaiyama aldol reaction7 with silyl ether 5 in presence of Lewis
acid catalysis to yield enone 12 as a mixture of diastereomers
(dr = 85:15) separated by simple column chromatography in 75%
yield. The syn-selective reduction8 of major isomer 12 with Et2-
BOMe and sodium borohydride at ꢀ78 °C gave syn-diol 13 along
with its inseparable minor isomer (dr = 91:9) in 90% yield which
were separated in the next step. Mixture of both diastereomers
were subjected to 2,2-dimethoxypropane/ PPTS to afford acetonide
3 in 92% yield (Scheme 1).
Fig. 2. Retrosynthetic analysis.
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S. Paladugu et al. / Tetrahedron Letters xxx (2017) xxx–xxx
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Scheme 1. Synthesis of intermediate 3.
Scheme 2. Synthesis of the C1—C9 fragment.
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S. Paladugu et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Scheme 3. Synthesis of the C1—C10 fragment.
Scheme 4. Synthesis of advanced intermediate 2.
Conclusions
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Please cite this article in press as: Paladugu S., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.06.011