Concise synthesis of the tricyclic core of platencin

Article abstract of DOI:10.1002/anie.200801587

(Chemical Equation Presented) A radical change: Implementation of a radical-mediated rearrangement of the bicyclo[3.2.1]octyl moiety to the bicyclo-[2.2.2]octane structure has enabled a concise synthesis of the tricyclic core of platencin, a newly discove

Full text of DOI:10.1002/anie.200801587

Angewandte
Chemie
DOI: 10.1002/anie.200801587
Natural Products
Concise Synthesis of the Tricyclic Core of Platencin**
Sang Young Yun, Jun-Cheng Zheng, and Daesung Lee*
Platensimycin (1)[1] and platencin (2),[2] which are structurally
related antibiotics, were recently discovered through a
systematic target-based whole-cell high-throughput screen-
three-carbon homologation followed by formation of an
amide bond with 3-amino-2,4-dihydroxybenzoic acid.[6] An
intramolecular aldol reaction or ring-closing metathesis
(RCM) reaction is envisioned for the formation of cyclo-
hexenone moiety of 3 starting from ketoaldehyde 4 or from an
appropriate diene RCM precursor 5. These precursors would
be elaborated from 6 by a two-carbon homologation. A
skeletal rearrangement of the initially formed radical inter-
mediate 9 to the required bicyclo[2.2.2]octane 7 would be
initiated by the addition of a tributylstannyl radical to the
pendant alkyne moiety of precursor 10.[7] The cyclohexene-
ing. These novel bacterial metabolites show
potent Gram-positive antibacterial activity
against antibiotic-resistant pathogens.[3] Platen-
cin (2), isolated from a new strain of Streptomy-
ces platensis MA 7339 found in a soil sample
collected in Spain, exhibits MIC values in the
range 0.14–9.4 mm against S. aureus, MRSA, van-
comycin-resistant enterococci, and Steptococcus
pneumoniae. Further biochemical assays identi-
fied 2 as a potent and dual inhibitor of the fatty
acid biosynthesis condensing enzymes b-keto-
acyl-(acyl-carrier-protein) synthase II (FabF) and
III (FabH), with IC50 values of 1.95 and
3.91 mgmLÀ1, respectively.[2] As a result of the
promising antibacterial activities and novel struc-
tures of 1 and 2, many insightful synthetic
approaches have been developed since the first
total synthesis of platensimycin by Nicolaou
et al.[4,5] Recently, Nicolaou et al. also reported
the first total synthesis of platencin (2).[6] Herein,
we report a concise synthetic route to the tricyclic
core of platencin which relies on a radical-
mediated construction of the central bicyclo-
[2.2.2]octane moiety as the key feature.[7]
Our retrosynthetic plan for platencin (2) is
Scheme 1. Retrosynthetic analysis of platencin (2).
depicted in Scheme 1. Synthesis of the natural
product is expected to be completed by the final-
stage elaboration of the core 3 through a
based 1,6-enyne 10, in turn, could be prepared by desym-
metrization of meso-anhydride 12 to form lactone 11 followed
by propargylation.
[*]Dr. S. Y. Yun, Dr. J.-C. Zheng, Prof. D. Lee
Department of Chemistry
The preparation of radical ring-closure precursor 10
commenced with the conversion of cyclic anhydride 12 into
lactone 11 by reduction with DIBAL followed by treatment
with acid (Scheme 2). For the asymmetric synthesis, 12 was
desymmetrized to form the carboxylic acid half ester 13 by
using the procedure of Deng and co-workers.[8] Compound 13
was converted into acid chloride 14 and subsequently reduced
then lactonized to give 11.[9] Propargylation of 11 (LDA,
propargyl bromide) formed 15, which was subsequently
University of Illinois at Chicago
845 West Taylor Street, Chicago, IL 60607 (USA)
Fax: (+1)312-996-0431
E-mail: dsunglee@uic.edu
[**]We gratefully acknowledge the University of Illinois at Chicago for
their support. We thank Dr. Furong Sun (UIUC) for mass
spectrometry measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801587.
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Communications
Scheme 3. The intramolecular aldol approach: a) K2CO3 (2.5 equiv),
MeOH, 1 h, 96%; b) NaH (2 equiv), TBSCl (1 equiv), THF, À78 to RT
over 30 min, 90%; c) PCC (2 equiv), 4-Š M.S., CH2Cl2, 40 min;
d) Ph3PCH2OMeCl (2 equiv), nBuLi, THF, À78 to À208C over 30 min;
then À208C to RT over 30 min; e) NBS (1 equiv), THF/H2O (10:1),
08C, 1 h; aq NH4Cl, Zn (3 equiv); f) MeMgBr (1.5 equiv), THF, 08C,
30 min, 45% (ca. 1:1 mixture of diastereomers; over 4 steps); g) TBAF
(1.1 equiv), THF, 08C, 30 min, 85%; h) (COCl)2 (3 equiv), DMSO
(6 equiv), CH2Cl2, Et3N (6 equiv), À788C; i) NaOH (5 equiv), EtOH,
24 h, 60% (over 2 steps). DMSO=dimethyl sulfoxide; M.S.=molecular
sieves; NBS=N-bromosuccinimide; PCC=pyridinium chlorochromate;
TBAF=tetrabutylammonium fluoride; TBS=tert-butyldimethylsilyl.
(1 equiv) at low temperature (À788C) to provide a mixture of
16a and 16b (ca. 2:1) in excellent yield (90%).[11] Oxidation
of the primary alcohol of 16a followed by treatment with
triphenylmethoxymethylphophorane yielded methyl enol
ether 17. Attempted hydrolysis of 17 (2n HCl, THF)
proceeded through acid-catalyzed hydration to form 19 via
18. Gratifyingly, treatment of 17 with NBS in aqueous THF at
low temperature gave the a-bromoaldehyde, which was
directly treated with zinc powder to give aldehyde 20. The
addition of methyl Grignard reagent to 20 led to a separable
mixture of diastereomeric alcohols 21 (ca. 1:1; 45% overall
yield from 16a). Removal of the TBS group was followed by
global oxidation to give the corresponding ketoaldehyde 4,
Scheme 2. Construction of the bicyclo[2.2.2]octane moiety: a) DIBAL
(2.1 equiv), THF, À788C to RT over 1 h; 50% aq H2SO4, 08C, 4 h,
92%; b) LDA (1.1 equiv), THF, À788C; C3H3Br, À788C to RT over 1 h,
89%; c) LAH (1.5 equiv), THF, 08C, 1 h, 95%; d) Ac2O (2.2 equiv), Pyr,
DMAP, CH2Cl2, 30 min, 99%; e) Bu3SnH (1.5 equiv), AIBN, toluene,
1008C, 1 h; SiO2, 1008C, 30 min, 51% (R=H), 67% (R=Ac);
f) (DHQD)2AQN (A; 8 mol%), MeOH (10 equiv), Et2O, À208C, 72 h,
99%; g) (COCl)2 (6 equiv), CH2Cl2, À788C, 30 min; h) NaBH4
(2 equiv), MeOH, THF, À788C, 30 min; i) TsOH (12 mol%), toluene,
1008C, 8 h, 89% (over 3 steps). AIBN=azobisisobutyronitrile;
(DHQD)2AQN=bis(dihydroquinidine) anthraquinone; DIBAL=diiso-
butylaluminum hydride; DMAP=4-(dimethylamino)pyridine; LDA=
lithium diisopropylamide; LAH=lithium aluminum hydride; Pyr=pyr-
idine; Ts=para-toluenesulfonyl.
and
a
subsequent intramolecular aldol/dehydration[5g,6a]
afforded enone 3 in good yield (60% over 2 steps).
reduced and afforded 10a. An initial attempt at radical-
mediated cyclization of 10a provided bicyclo[2.2.2]octane 6a
in marginal yield (51%). The corresponding diacetate 10b
gave a slightly improved yield of 6b (67%) under the same
reaction conditions (Bu3SnH, AIBN, toluene, 1008C; then
SiO2).[10] The destannylation of 7 was efficiently achieved by
adding silica gel after completion of the reaction but before
cooling.
The final steps for the synthesis of enone 3 began with
mono protection of diol 6a (Scheme 3). Diacetate 6b was
converted into diol 6a (K2CO3, MeOH, 96%), which was then
treated with sodium hydride (2 equiv, THF) and TBSCl
Although 16b could be recycled to form 16a through a
deprotection/reprotection cycle, an RCM-based approach
was developed to facilitate the use of 16b. As shown in
Scheme 4, 16b was elaborated to 22 by a three-step sequence
involving oxidation with PCC, a Wittig reaction, and removal
of the TBS group (73% over 3 steps). One-carbon homo-
logation of 22 to give the corresponding unstable aldehyde 23
followed by addition of vinyl Grignard reagent set the stage
for RCM of the diene,[12] which delivered allylic alcohol 24 as
an inconsequential mixture (ca. 1:1) upon treatment with the
second-generation Grubbs catalyst.[13] Manganese dioxide
mediated oxidation of 24 afforded enone 3 in 86% yield. The
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Angewandte
Chemie
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Scheme 4. RCM approach for the construction of enone 3: a) PCC
(2 equiv), 4-Š M.S., CH2Cl2, 30 min; b) Ph3PCH3Br (3 equiv), nBuLi,
À78 to 08C over 30 min; then 08C, 30 min; c) TsOH (5 mol%),
MeOH, 1 h, 73% (over 3 steps); d) PCC (2 equiv), 4-Š M.S., CH2Cl2,
30 min; e) Ph3PCH2OMeCl (2.5 equiv), nBuLi, THF, À78 to À208C
over 30 min; then À208C to RT over 30 min; NBS (1 equiv), THF/H2O
(10:1), À20 to 08C over 1 h; then aq NH4Cl, Zn (3 equiv);
f) VinylMgBr (1.5 equiv), THF, 08C, 1 h, 39% (ca. 1:1 mixture of
diastereomers; over 4 steps); g) Grubbs II catalyst (5 mol%), CH2Cl2,
408C, 4 h, 95%; h) MnO2 (8 equiv), CH2Cl2, 1 h, 86%.
1H and 13C NMR spectra of 3 are identical to those reported
by Nicolaou et al.[6a]
In conclusion, we have achieved a concise synthesis
(14 steps in the shortest sequence with 10% overall yield)
of the bridged tricyclic enone core 3, a key advanced
intermediate in the total synthesis of platencin by Nicolaou
et al. Our route highlights the radical-mediated construction
of a key building block through a skeletal rearrangement. An
intramolecular aldol reaction and an RCM reaction were
employed to complete the core cyclohexenone moiety of
platencin. A Lewis base catalyzed desymmetrization of a
cyclic anhydride was utilized to introduce appropriate chi-
rality. We are currently pursuing the asymmetric total syn-
thesis of both platencin and platensimycin starting from chiral
building block 15.
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[10] Please see the Supporting Information for details.
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Received: April 4, 2008
Published online: June 11, 2008
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Keywords: antibiotics · natural products · radical cyclization ·
ring-closing metathesis · total synthesis
.
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Angew. Chem. Int. Ed. 2008, 47, 6201 –6203
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