Synthesis of streptolydigin, a potent bacterial RNA polymerase inhibitor

Article abstract of DOI:10.1021/ja107190w

Streptolydigin is a highly potent, broad-spectrum antibiotic produced by Streptomyces lydicus, which inhibits bacterial RNA polymerase. We describe the first synthesis of streptolydigin, which was assembled in a highly convergent and fully stereocontrolle

Full text of DOI:10.1021/ja107190w

Published on Web 09/29/2010
Synthesis of Streptolydigin, a Potent Bacterial RNA Polymerase Inhibitor
Sergey V. Pronin and Sergey A. Kozmin*
UniVersity of Chicago, Department of Chemistry, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received August 10, 2010; E-mail: skozmin@uchicago.edu
Scheme 1
Abstract: Streptolydigin is a highly potent, broad-spectrum
antibiotic produced by Streptomyces lydicus, which inhibits
bacterial RNA polymerase. We describe the first synthesis of
streptolydigin, which was assembled in a highly convergent
and fully stereocontrolled fashion with a longest linear se-
quence of 24 steps starting from commercially available
precursors. The assembly process entailed preparation of fully
elaborated streptolic and ydiginic subunits of the natural
product, followed by a highly efficient union in a three-step one-
pot procedure, which included Dieckmann cyclization with a
concomitant imide opening, Horner-Wadsworth-Emmons ole-
fination, and desilylation.
In 1956, researchers from Upjohn described the isolation and
broad-spectrum antibiotic activity of streptolydigin (1).1 This
natural product acts as a potent inhibitor of bacterial RNA
polymerase (RNAP) by preventing the nucleotide triphosphate
insertion step.2,3 The biochemical mechanism of RNAP inhibi-
tion by streptolydigin is distinct from that of clinically used
rifamycin antibiotics that are particularly important for treatment
of tuberculosis.4 The different mode of interaction of streptoly-
digin and rifamycins with RNAP results in essentially no cross-
resistance5 and is noteworthy in considering possible applica-
tions. The structure of streptolydigin was determined by the
Rinehart group.6 This seminal effort revealed the complex
molecular architecture of the natural product, which is comprised
of an epoxide-containing bicyclic ketal connected by a polyene
spacer to a glycosylated, highly functionalized acyl tetramic acid
(Scheme 1). Compared to other structurally related natural
products, including tirandalydigin and tirandamycins,7 strep-
tolydigin has the most complex structure and highest antibacterial
activity within this class of antibiotics.8 While several syntheses
of tirandamycins9 and a protected form of tirandalydigin10 have
been reported, the solution of the streptolydigin synthetic
problem has not been described despite the preparation of two
separate degradation subunits known as streptolic and ydiginic
acids.11,10 In this communication, we present the first synthesis
of streptolydigin, which was assembled with a longest linear
sequence of 24 steps starting from commercially available
precursors.
aldehyde 2. The bicyclic framework of 2 would be constructed
from lactone 5, which in turn would arise from esterification of
acid 8 with diol 9, followed by ring-closing metathesis. Imide 6
and protected rhodinose 7 would derive from acyclic precursors
10 and 11, respectively.
The assembly process began with the preparation of unsatur-
ated acid 8 (Scheme 2). Catalytic asymmetric dihydroxylation14
of benzyl enoate 1215 proceeded in 92% ee. Acetalization of
the resulting triol occurred chemoselectively at the primary and
tertiary alcohols enabling the conversion of the remaining
secondary alcohol into the corresponding triflate. Subsequent
elimination with DBU and final saponification furnished car-
boxylic acid 8. Preparation of diol 9 began with a diastereose-
lective aldol reaction of crotonaldehyde 13 with titanium enolate
derived from benzyloxyketone 14,16 followed by the Evans-
Tishchenko reduction17 and saponification of the resulting
acetate. Chemoselective acylation of diol 9 with acid 8 proceeded
successfully using DCC and DMAP to give ester 15. Removal
of the acetonide and silyl protection of the primary alcohol
afforded the diene, which underwent the ring-closing metathesis
upon exposure to the Hoveyda-Grubbs catalyst 16.18 Lactone
5 was next converted into the Weinreb amide, which was treated
with methyllithium and subjected to acid-mediated intramolecular
ketalization to give the only expected bicyclic acetal 17.
Reductive cleavage of the benzyl ether, followed by oxidation
and olefination, furnished ester 18, which was subjected to
DIBAL reduction, silylation of the resulting primary alcohol,
The initial disconnection of streptolydigin (1) was designed
to unite three advanced fragments, including bicyclic aldehyde
2, diethylphosphono-3-oxobutanthioate 3,12 and N-glycosyl imide
4 (Scheme 1). The assembly process would entail N-acylation
of 4 with 3, Dieckmann cyclization with a concomitant imide
opening, which followed the pioneering work of Rinehart,13 and
Horner-Wadsworth-Emmons olefination, which was particu-
larly successful during the assembly of tirandomycins.9 The main
challenge was to ensure that our assembly process would be
compatible with the highly labile terminal epoxide moiety of
9
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10.1021/ja107190w  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Scheme 3
and chemoselective TIPS deprotection using LiAlH4. Treatment
of diol 19 with Tf2O and pyridine, followed by DBU, induced
efficient epoxide formation. Subsequent fluoride-mediated desi-
lylation and Dess-Martin oxidation afforded aldehyde 2.
Preparation of aspartimide 6 began with conversion of acid 2019
to the corresponding N-acyloxazolidinone, followed by diastereo-
selective azide transfer (Scheme 3).20 Treatment of the resulting
imide 22 with methylamine and hydrogenation in the presence of
Boc2O gave alcohol 23, which underwent TEMPO-catalyzed
oxidative cyclization and Boc-deprotection with TFA to afford the
required primary amine 6.
Supporting Information Available: Complete ref 3b and experi-
mental details. This information is available free of charge via the
Internet at http://pubs.acs.org.
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