Studies directed towards the total synthesis of narbonolide: Stereoselective synthesis of the C1-C15 chain

Article abstract of DOI:10.1016/j.tetlet.2013.04.023

A stereoselective synthesis of the C1-C15 chain of narbonolide, a 14-membered macrolactone belonging to the pikromycin family of antibiotics is described. The key steps involved in this synthesis are desymmetrization of bicyclic olefin with Brown's asymmetric hydroboration, Evans aldol reaction, Takai olefination and Yamaguchi esterification to yield the corresponding ester.

Full text of DOI:10.1016/j.tetlet.2013.04.023

Tetrahedron Letters 54 (2013) 3329–3331
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Tetrahedron Letters
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Studies directed towards the total synthesis of narbonolide: stereoselective
synthesis of the C1–C15 chain
⇑
Jhillu S. Yadav , Aala Kavita, Kovvuri V. Raghavendra Rao, Debendra K. Mohapatra
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 February 2013
Revised 5 April 2013
Accepted 7 April 2013
Available online 13 April 2013
A stereoselective synthesis of the C1–C15 chain of narbonolide, a 14-membered macrolactone belonging
to the pikromycin family of antibiotics is described. The key steps involved in this synthesis are desym-
metrization of bicyclic olefin with Brown’s asymmetric hydroboration, Evans aldol reaction, Takai olefin-
ation and Yamaguchi esterification to yield the corresponding ester.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Macrolactone
Narbonolide
Desymmetrization
Evans aldol reaction
Yamaguchi esterification
Polyketides and polypropionates represent a remarkable class
of natural compounds1 that exhibit astonishing range of structural
complexity and functional diversity, as well as broad potential for
pharmacological applications.2 These macrolide antibiotics show a
variety of biological activities including a detailed understanding
of biosynthesis, endless chemical diversity and used for the treat-
ment of drug-resistant bacterial infections and intestinal motility
disorders.3 Stereocontrolled synthesis of macrolide antibiotics is
one of the significant areas in current synthetic organic chemistry,
and various novel synthetic methodologies have been established
for the successful total synthesis of such complex natural products.
Streptomyces venezuelae produces two major types of macrolide
antibiotics, that is, the methymycin and pikromycin families,
which contain the 12- and 14-membered macrolactones as agly-
cones, respectively. Aglycones of the pikromycin family that have
14-membered lactones are narbonolide, pikronolide, neopikrono-
lide and novapikronolide, respectively. The structures of these
macrolides vary depending on the oxidation pattern during the
post-PKS modification of narbonolide (1). Concurrent to its impor-
tant biological studies, many organic chemists began showing
interest in the synthesis of these natural products.4,5
rization of bicyclic olefin and substrate-controlled stereoselective
transformations to create contiguous stereocenters. This strategy
was successfully employed in our laboratory for the total synthesis
of several complex biologically potent and structurally novel natu-
ral products.6 In this Letter, we report a highly stereoselective syn-
thesis of the C1–C15 fragment of narbonolide following
desymmetrization strategy (Fig. 1).
a
For the synthesis of narbonolide (1), the 14-membered macro-
lactone was retrosynthetically divided into fragments 3 and 4 as
shown in Scheme 1. These two fragments could be coupled by
using Yamaguchi esterification protocol to achieve the synthesis
of 2. Further, the key fragment 3 could be synthesized from triol
5, which could be easily achieved from bicyclic alcohol 6 through
desymmetrization using Brown’s asymmetric hydroboration and
subsequent substrate controlled transformations7 (Scheme 1)
whereas vinyl iodide compound 4 could be obtained through Takai
olefination.
O
9
The stereoselective synthesis for the C1–C15 chain of narbono-
lide (1) is considered to be of interest, as our research group has
explored the potential of desymmetrization strategy in natural
product synthesis. Our approach generally involves the desymmet-
5
12
O
OH
1
3
15
O
O
⇑
Narbonolide (1)
Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
E-mail addresses: yadavpub@iict.res.in (J.S. Yadav), mohapatra@iict.res.in (D.K.
Mohapatra).
Figure 1. Structure of narbonolide (1).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.023

3330
J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 3329–3331
As shown in Scheme 2, synthesis of the key fragment 3 began
protected by using dimethyl acetal of p-methoxy benzaldehyde8
in the presence of catalytic amount of CSA in dichloromethane at
0 °C to afford p-methoxy benzylidene acetal 7 (85%) and the free
hydroxy group was silylated with TBDPS-Cl to furnish the fully
protected triol 8 in 87% yield.
with triol 5, which was synthesized from the bicyclic precursor 6
using our own developed protocol.7 Triol 5 was then selectively
O
H
O
I
OH
PMBO
OH
1a
O
O
I
O
OH
4
OH
O
O
2,4,6-Trichlorobenzoyl chloride
TBDPSO
TBDPSO
PMBO
OTBSO
O
Et3N, DMAP, toluene
0 °C to rt, 2h, 80%
Narbonolide (1)
I
3
PMBO
OH
O
OH
2
O
TBAF, THF
I
OH
OH
OTBSO
14
89%
PMBO
I
TBDPSO
PMBO
OTBSO
O
3
4
O
O
O
I
O
O
OH
HO
PMBO
OH
O
OH
OH
OH
2
OH
Narbonolide (1)
6
5
Scheme 1. Retrosynthetic analysis.
Scheme 3. Synthesis of the fragment 2.
O
PMB-Acetal
Ref. 6
CSA, CH2Cl2, 85%
OH
OH OH
OH
O
5
6
7
TBDPS-Cl
imidazole
CH2Cl2, 87%
DIBAL-H
OTBDPS
O
O
OH
O
CH2Cl2, -15 °C
89%
8
O
O
Bn
a) Dess-Martin
periodinane, CH2Cl2
S
OH
N
b) 10, TiCl4, (-)-Spartenine
OTBDPS OPMB
S
O
TBDPSO
OH
11
PMBO
CH2Cl2, 0 °C, 2h, 85%
Bn
9
over 2 steps
S
10
N
S
O
Bn
S
NaBH4, MeOH
rt, 3 h, 86%
TBSOTf, 2, 6-lutidine
CH2Cl2, 0 oC, 85%
N
S
O
TBDPSO
PMBO
OTBS
12
a) Dess-Martin
periodinane,
CH2Cl2, 1 h
OH
b) NaClO2, NaH2PO4
t-BuOH, H2O (3:1)
2-Methyl-2-butene
87% over two steps
TBDPSO
PMBO
OTBSO
TBDPSO
PMBO
OTBSOH
3
13
Scheme 2. Synthesis of the fragment 3.

J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 3329–3331
3331
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Regioselective reductive ring-opening of the PMB acetal using
DIBAL-H at À15 °C in dichloromethane provided primary alcohol
9 (89%).9 Oxidation of the primary alcohol with Dess–Martin peri-
odinane10 in the presence of NaHCO3 at 0 °C furnished the alde-
hyde, which was subjected to asymmetric aldol reaction with
chiral N-acylthiazolidinethione 10 under TiCl4 and (À)-sparteine
conditions to yield the required syn aldol adduct 11 in 85% yield
over two steps.11 The free OH group in syn aldol adduct 11 was
silylated by using TBDMSOTf and 2,6-lutidine at 0 °C to obtain
TBS-protected compound 12 in 85% yield.12 Compound 12 was
subjected to NaBH4 in MeOH to obtain the desired primary alcohol
13 in 86% yield (Scheme 2). The alcohol was oxidized with Dess–
Martin periodinane to obtain the aldehyde, which on further oxi-
dation under Pinnick conditions (NaClO2, NaH2PO4Á2H2O) afforded
the corresponding acid 3 in 87% yield over two steps (Scheme 3).13
The esterification of carboxylic acid 3 with hydroxy compound
4,14 under Yamaguchi conditions was achieved to obtain the corre-
sponding ester 14 in 80% yield.15 Desilylation of both TBDPS and
TBS groups with TBAF in THF furnished diol 2 in 89% yield.
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In conclusion, we have completed the synthesis of the C1–C15
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high diastereoselectivity. Aldol reaction of propanal followed by
Takai olefination furnished the enriched trans iodo compound 4,
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Acknowledgments
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A.K. and K.V.R.R. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial assistance in the
form of research fellowship.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.023.
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