Enantioselective total synthesis of bioactive natural product (+)-Sch 642305: A structurally novel inhibitor of bacterial DNA primase and HIV-1 Tat transactivation

Article abstract of DOI:10.1039/b505264e

The total synthesis of the bioactive natural product (+)-Sch 642305 has been achieved from a readily available chiral building block using an RCM protocol to construct the key decalactone moiety; our approach is notable for its built-in flexibility and is

Full text of DOI:10.1039/b505264e

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Enantioselective total synthesis of bioactive natural product (+)-Sch
642305: a structurally novel inhibitor of bacterial DNA primase and
HIV-1 Tat transactivation{
Goverdhan Mehta* and Harish M. Shinde
Received (in Cambridge, UK) 14th April 2005, Accepted 18th May 2005
First published as an Advance Article on the web 10th June 2005
DOI: 10.1039/b505264e
Penicillium verrucosum (culture ILF-16214).4 The absolute configu-
The total synthesis of the bioactive natural product (+)-Sch
ration of 1 was determined through the anomalous diffraction
effects in the X-ray crystallographic analysis of its p-bromobenzo-
ate derivative. Besides its structural novelty, 1 exhibited inhibitory
activity against Escherichia coli bacterial DNA primase enzyme
with an EC50 value of 70mM. It may also be pointed out that very
few natural products exhibiting DnaG inhibition activity have
been reported so far; with the notable exception of phenolic
saccharides isolated recently from the Peruvian plant Polygonum
cuspidatum sp.5 In addition to its bacterial DNA primase
inhibitory activity, a very recent report from a group at Merck
indicates that Sch 642305 1, isolated this time from the fungus
Septofusidium sp., exhibits inhibition of HIV-1 Tat-dependent
transactivation with an IC50 value of 1.00 mM.6 HIV-1 Tat is one
of the six regulatory proteins encoded by HIV and is essential for
viral replication.7 Tat-protein therefore is an attractive target for
the development of new therapeutics for the treatment of HIV
infection.6
642305 has been achieved from a readily available chiral
building block using an RCM protocol to construct the key
decalactone moiety; our approach is notable for its built-in
flexibility and is diversity oriented.
Bacterial infections constitute a serious threat to human health
worldwide due to the rapid emergence of antibiotic-resistant
strains, underscoring the urgent need for the development of new
classes of antibacterial agents.1 In this context, target and
mechanism-based drug discovery methods, utilizing both natural
products and synthetic libraries, are being explored in the search
for alternative antibacterial therapeutics. Bacterial DNA primase
(DnaG) is a DNA-dependent RNA polymerase that is crucial for
the replication of bacterial chromosomal DNA.2 Genetic valida-
tion of DnaG indicated that the inhibition of bacterial primase
causes a rapid bactericidal response.3 In the intricate process of
DNA replication, DnaG has a pivotal role in initiating the ss RNA
primer synthesis. It has been established that, while the replication
of the leading-strand DNA requires only one RNA primer, that of
the lagging strand DNA requires .2000 primer sites.
Consequently, interruption of the RNA primer synthesis would
eventuate in a catastrophic event in bacterial chromosome
replication. Thus, DNA primase has emerged as a promising
target for the discovery of new antibacterial drugs and its
inhibition is an area of high priority pursuits.4,5
The varied range of potent biological activity shown by 1
justifies the development of synthetic routes to harness its
potential, to serve as a platform for diversity generation and
inhibitory activity modulation. From a purely structural perspec-
tive, the functionally-embellished bicyclic macrolide framework of
1, composed of a decalactone moiety fused to a 4-hydroxycyclo-
hexenone ring, is new among natural products and the additional
presence of four stereogenic centers makes it a challenging and
Towards the end of 2003, scientists at Schering-Plough reported
the isolation and structure elucidation of a novel natural product,
Sch 642305 1 (Fig. 1), from the fermentation broth of the fungus
Fig. 1
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India. E-mail: gm@orgchem.iisc.ernet.in;
Fax: +91-80- 23600936; Tel: +91-80-22932850
Scheme 1 Reagents and conditions: i, NaBH4, CeCl3, MeOH, 0 uC,
15 min, 90%; ii, lipase PS-D, vinyl acetate, THF, RT, 82%; iii, TBSCl,
imidazole, DMAP, DMF, 6 h, 94%; iv, K2CO3, MeOH, 0 uC, 5 h; v, PDC,
4 s MS, DCM, 1 h, 0 uC (90% for two steps).
{ Electronic supplementary information (ESI) available: 1H-NMR and
13C-NMR spectral data of all new compounds, and copies of H-NMR
1
and 13C-NMR spectra of compounds (+)-6, (2)-11, (+)-16 and (+)-1. See
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Scheme 2 Reagents and conditions: i, Zn, allyl bromide, sonication,
THF, 10 min, 93%; ii, KH, dioxane, 85 uC, 30 min, 81%; iii, diphenyl
ether, 210 uC, 15 min, 85%; iv, LDA, BrCH2CO2Et, HMPA, THF,
278 uC, 69%.
Scheme 3 Reagents and conditions: i, NaBH4, CeCl3, MeOH, 250 uC,
15 min, 80%, a : b-OH 5 1 : 1.2; ii, PDC, 4 s MS, DCM, 1 h, 0 uC, 92%;
iii, TBDPSCl, imidazole, DMAP, DMF, 93%; iv, (S)-(+)-4-pentene-2-ol,
Ti(OiPr)4, 90 uC, 91%.
attractive synthetic proposition. We report here a short, enantio-
selective total synthesis of Sch 642305 1, which deploys an RCM
protocol to construct the key decalactone moiety.
(+)-6 and set up the stage for an oxy-Cope rearrangement,
Scheme 2.9 Anionic activation of (+)-6 led to the contemplated [3,3]
sigmatropic shift to provide the desired allylated product (2)-7 as
a single diastereoisomer.9,10 At this juncture, the norbornyl scaffold
was disengaged through a retro-Diels–Alder process to furnish the
cyclohexenone (2)-8.9 Regio- and stereoselective alkylation of
(2)-8 with ethyl bromoacetate led to (2)-9 with the requisite
trans-disposition of the two side arms (Scheme 2).11
Luche reduction12 of (2)-9 furnished a mixture (1 : 1.2) of
diastereomeric alcohols (2)-10 and (2)-11, of which the latter had
the requisite C4 stereochemistry of the natural product.9 However,
the unwanted stereoisomer (2)-10 was also serviceable through
recycling via PDC oxidation to (2)-9 (Scheme 3). The hydroxyl
group in (2)-11 was protected as the TBDPS derivative (+)-12 and
Our synthesis of Sch 642305 1 commenced from the readily
accessible (and commercially available) endo-tricyclic Diels–Alder
adduct 2 of cyclopentadiene and p-benzoquinone. Our initial
objective was to render 2 chiral and chemo-differentiate the two
carbonyl groups in the pendent cyclohexanoid ring. Stereoselective
reduction of the carbonyl groups in 2 led to the meso,endo,endo-
diol 3 which, on lipase-mediated enzymatic desymmetrization,
furnished enantiopure monoacetate (+)-4 (y99% ee) as described
previously (Scheme 1).8 Further functional group transformations
to (+)-4 delivered the key building block (+)-5 quite conveniently.
Zinc-mediated Barbier-type allylation of (+)-5 proceeded
smoothly and stereoselectively with exo-face selectivity, to deliver
Scheme 4 Reagents and conditions: i, Grubbs II catalyst (14) (10 mol%), DCM, reflux, 2 h, 84%; ii, PdCl2(CH3CN)2, moist acetone, rt, 5 h, 94%; iii, Dess–
Martin periodinane, DCM, 0 uC, 6 h, 95%; iv, 10% Pd/C, H2, EtOAc, 96%; v, LHMDS, PhSeCl, THF, 278 uC; vi, H2O2, pyridine, DCM, 0 uC, 10 min
(78% for two steps); vii, TBAF–AcOH (1 : 1), THF, RT, 8 h, 91%.
3704 | Chem. Commun., 2005, 3703–3705
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the ethyl ester moiety was subjected to transesterification with the
matched (S)-4-pentene-2-ol to furnish (+)-13 (Scheme 3).9,13
In (+)-13, we had the precursor well poised for implementing the
key RCM protocol. Indeed, exposure of (+)-13 to the second
generation Grubbs catalyst 1414 resulted in the smooth generation
of the bicyclic framework (+)-15 embodying the decalactone
moiety (Scheme 4). At this stage, the logical endeavour was to
selectively reduce the cyclodecene double bond but this proved to
be quite difficult despite many variations in the catalyst and
hydrogenation conditions. Consequently, an alternate strategy
was devised. Pd(II)-mediated chemoselective TBS-deprotection15 of
(+)-15 and subsequent oxidation of the generated hydroxyl
functionality with Dess–Martin periodinane16 delivered the enone
(+)-16.9 Catalytic hydrogenation of (+)-16 led to the fully saturated
bicycle (2)-17 in which the enone double bond needed to be
Notes and references
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1135; (c) G. Mehta and K. Islam, Synlett, 2000, 1473.
9 All new compounds were fully characterized on the basis of their IR,
1H-NMR, 13C-NMR, and HRMS data (see ESI{).
10 For an anion-assisted sigmatropic rearrangements, see: S. R. Wilson,
Org. React., 1993, 43, 93.
11 K. F. Podraza and R. L. Bassfield, J. Org. Chem., 1989, 54, 5919.
12 A. L. Gemal and J. L. Luche, J. Am. Chem. Soc., 1981, 103,
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14 (a) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953; (b) For recent reviews on RCM, see: (i) A. Fu¨rstner, Angew. Chem.,
Int. Ed., 2000, 39, 3012; (ii) T. M. Trnka and R. H. Grubbs, Acc. Chem.
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restored.9 This was accomplished via
a phenylselenation–
selenoxide elimination sequence.17 Thus, phenylselenation of
(2)-17 was effected under kinetically controlled conditions to give
an a-phenylseleno compound which was directly oxidized with
hydrogen peroxide to deliver the penultimate product (+)-18
(Scheme 4).9 Finally, the TBDPS protection in (+)-18 was carefully
removed with TBAF buffered with an equimolar amount of acetic
acid,18 to furnish the target molecule Sch 642305 (+)-1. Our
synthetic (+)-1 was found to be spectroscopically identical to the
natural product (see ESI{) and its [a]D + 71.0u (c, 0.31, CH3OH)
matched well with the reported values of [a]D + 67.44u (c, 0.50,
CH3OH) for (+)-1.4
In summary, we have accomplished the first total synthesis of
the bioactive natural product Sch 642305 (+)-1, through a concise,
stereo- and enantioselective strategy which lends itself amenable to
diversity creation for further exploring its therapeutic potential in
the light of promising initial leads.
We thank Mr Atsuya Hirano and Mr Tan Nakagawa, Amano
Enzyme Co., Nagoya, Japan for their generous gift of lipase PS-D.
HMS, thanks CSIR, India for the award of a research fellowship.
This research was supported by the Chemical Biology Unit of the
JNCASR in Bangalore.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3703–3705 | 3705