A chiral pool based synthesis of platensimycin

Article abstract of DOI:10.1002/anie.200705080

(Chemical Equation Presented) Extensive pharming: An expedient entry into the tetracycle 2, a late-stage synthetic intermediate en route to the broad-spectrum antibiotic (-)-platensimycin (1) has been accomplished. The strategy involves a series of cyclizations starting from the inexpensive chiral pool starting material (R)-(-)-carvone.

Full text of DOI:10.1002/anie.200705080

Communications
DOI: 10.1002/anie.200705080
Natural Products
A Chiral Pool Based Synthesis of Platensimycin**
K. C. Nicolaou,* Doron Pappo, Kit Y. Tsang, Romelo Gibe, and David Y.-K. Chen*
The fight against infectious disease rages on as scientists
continue their struggle to overcome the emergence of drug
resistance through new discoveries in chemistry and biology.[1]
The recent discovery of platensimycin (1, Scheme 1) by a
Merckresearch team is a beautiful illustration of how natural
products chemistry combined with modern biological tech-
niques can lead to important developments in the search for
new antibiotics.[2] Platensimycin (1) was identified by high-
throughput screening and RNA silencing technologies as a
potent and selective inhibitor of the b-ketoacyl-(acyl-carrier-
protein) synthase (FabF). Flexible synthetic routes to platen-
simycin may be particularly useful in accessing novel ana-
logues that may prove superior to the natural product with
regard to its pharmacological properties.[3] Herein we report a
new synthetic strategy that leads from the readily available
and inexpensive (R)-(ꢀ)-carvone (7) to the tetracyclic enone
2—a convenient precursor to platensimycin (1).
Scheme 1 outlines, in retrosynthetic format, the overall
plan for the construction of the required enone 2 starting from
(R)-(ꢀ)-carvone (7). Thus, enone 2 was expected to arise from
tricyclic ketone 3, whose connection to bicyclic keto aldehyde
4 could be recognized through a retro-anionic or radical 1,4-
addition reaction. The origins of 4 were then traced to
hydroxy keto acetal 5 by standard functional-group manipu-
Scheme 1. Structure and retrosynthetic analysis of (ꢀ)-platensimycin
(1).
lations. Finally, 5 was envisioned to arise from enone 6
through a radical-based ring closure, with the latter inter-
mediate being readily traced backto ( R)-(ꢀ)-carvone (7)
through a retro-Grignard reaction.
According to the synthetic blueprint, the synthesis of 2
began from (R)-(ꢀ)-carvone (7, Scheme 2). Thus, 1,2-addition
of Grignard reagent 8 to (ꢀ)-carvone (7) under Luche
conditions (CeCl3)[4] led to the corresponding tertiary alcohol,
which was directly oxidized (PCC) without further purifica-
tion to afford enone 6 in 90% yield for the two steps.
Intramolecular radical cyclization within the substituted
carvone 6 with concomitant construction of the C8 quaternary
center was accomplished through application of the sequen-
tial oxymercuration/reductive-alkylation methodology pio-
neered by Giese.[5] In this instance, treatment of 6 with
Hg(OAc)2 resulted in selective Markovnikov oxymercuration
of the geminal disubstituted alkene. The intermediate organo-
mercurial species was then reduced with NaBH4, presumably
leading to the corresponding primary radical, which under-
went 1,4-addition onto the enone system, thereby furnishing a
mixture (ca. 1:1) of exo (5a) and endo (5b, existing predom-
inantly as its hemiketal form 5b’; 5b’/5b ca. 6:1) alcohols in
61% yield. Dehydration of a mixture of 5a + 5b/5b’ with
Martinꢀs sulfurane[6a,b] led to exocyclic alkene 9,[6c] which was
subjected to a regioselective silyl enol ether formation (TMSI,
HMDS) followed by an electrophilic quench with PhSeCl,
and subsequent oxidative elimination (H2O2) to give enone 10
in 36% yield from 5a + 5b/5b’. Finally, unveiling of the
dioxane-masked aldehyde in 10 was achieved under micro-
[*] Prof. Dr. K. C. Nicolaou, Dr. D. Pappo, Dr. K. Y. Tsang, Dr. R. Gibe,
Dr. D. Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis
Institute of Chemical and Engineering Sciences (ICES)
Agency for Science, Technology and Research (A*STAR)
11 Biopolis Way, The Helios Block, no. 03-08, Singapore 138667
(Singapore)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
david_chen@ices.a-star.edu.sg
Prof. Dr. K. C. Nicolaou
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Doris Tan (ICES) for high-resolution mass-spectrometric
(HRMS) assistance. Financial support for this work was provided by
A*STAR, Singapore.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Scheme 2. Synthesis of dienone aldehyde 4. Reagents and conditions:
a) CeCl3 (1.1 equiv), THF, 1 h; then 8 (1.0 equiv), 0!238C, 3 h;
b) PCC (2.2 equiv), silica gel, CH2Cl2, 2 h, 90% for the two steps;
c) Hg(OAc)2 (1.1 equiv), THF/H2O (1:1), 238C, 30 min, NaBH4
(0.8 equiv), 208C, 45 min, 5a: 31%, 5b/5b’: 30%, 6: 20%; d) Martin’s
sulfurane (1.1 equiv), CH2Cl2, 238C, 12 h; e) LiI (2.5 equiv), TMSCl
(2.5 equiv), HMDS (5.0 equiv), CH2Cl2, ꢀ35!238C, 3 h; then PhSeCl
(1.15 equiv), CH2Cl2, ꢀ788C, 30 min, 42% for the two steps; f) 30%
aq H2O2 (10.0 equiv), Py (2.5 equiv), CH2Cl2, 08C, 1.5 h, 85%;
g) AcOH/H2O (5:1), 808C, microwave, 65 min, 85%. PCC=pyridinium
chlorochromate; TMS=trimethylsilyl; HMDS=hexamethyldisilazane;
Py=pyridine.
Scheme 3. Synthesis of tetracyclic enone 2. Reagents and conditions:
a) 11 (0.2 equiv), Et3N (1.2 equiv), EtOH, 808C, 18 h, 65% (3a/3b
ca. 5:1); b) SmI2 (0.1m in THF, 2.2 equiv), MeOH (2.5 equiv), 238C,
THF (0.032m), 2 min, 57%; c) p-nitrobenzoic acid (1.5 equiv), PPh3
(1.5 equiv), DIAD (3.4 equiv), benzene, 238C, 2 h, 67%; d) KOH (10%
in MeOH), 508C, 5 h, 14a: 46%, 14b: 45%; e) L-selectride (1.0m in
THF, 4.0 equiv), THF, ꢀ78!238C, 2 h; then 1n aq HCl, 0!238C, 2 h,
80%; f) PCC (2.0 equiv), CH2Cl2, 238C, 1.5 h, 95%; g) TMSCl
(3.3 equiv), LiI (3.3 equiv), HMDS (5.0 equiv), CH2Cl2, 08C, 3 h;
h) 1. IBX (1.5 equiv), MPO (1.5 equiv), DMSO, 238C, 2 h, 2: 53%, 17:
26%; or 2. Pd(OAc)2 (1.0 equiv), CH3CN, 238C, 5 h, 2: 60%, 17: 30%;
DIAD=diisopropyl azodicarboxylate; IBX=o-iodoxybenzoic acid;
MPO=4-methoxypyridine-N-oxide.
wave-irradiation conditions in AcOH/H2O (5:1) at 808C to
furnish dienone aldehyde 4 in 85% yield.
The next objective was the forging of the final carbocyclic
ring within the tetracyclic skeleton of 2. For the accomplish-
ment of this goal, an intramolecular Stetter reaction[3d,7] and a
SmI2-mediated[3a,8] radical cyclization were the available
options. Thus, a Stetter reaction of aldehyde 4 catalyzed by
thiazolium salt 11[7] in an ethanolic solution containing Et3N
yielded an inseparable mixture of C9 epimeric diketones 3a
and 3b in 65% combined yield (3a/3b ca. 5:1; scheme 3).
Interestingly, however, treatment of 4 with SmI2 in THF/
MeOH at room temperature resulted in the formation of
hydroxy ketone 12 possessing the undesired C9 configuration
as a single stereoisomer in 57% yield. A chelated transition
state (18, Scheme 4a) is postulated as a plausible explanation
for this highly stereoselective process. Accessing greater
quantities of the desired C9 stereoisomer was realized
While diketone 3a proved unstable and hydroxy ketone 12
appeared resistant to epimerization under the basic condi-
tions employed (KOH/MeOH), ester ketone 13, obtained
through Mitsunobu inversion of the C5 hydroxy group
(p-NO2C6H4CO2H/DIAD/PPh3, 67% yield) within 12, under-
went smooth and facile equilibration in the presence of KOH
with concomitant p-nitrobenzoate ester hydrolysis, to afford a
readily separable mixture of C9 epimers (14a/14b ca. 1.1:1,
91% yield). As seen in Scheme 4, this substrate-dependent
epimerization could be rationalized by the apparent slight
preference for the equatorially oriented C5 hydroxy group,
through
a base-mediated (KOH) equilibration process.
Angew. Chem. Int. Ed. 2008, 47, 944 –946
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Communications
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transformation on both 5a and 5b/5b’.
Scheme 4. a) Postulated samarium-templated ring closure of radical
18 to form hydroxy ketone 12; and b) base-mediated equilibration of of
hydroxy ketones 14a and 14b.
hence the reluctance of hydroxy ketone 12 to undergo the
similar equilibration process (see Scheme 4b). In preparation
for the casting of the remaining tetrahydrofuran system,
stereoselective reduction of the C10 ketone within 14b was
carried out with L-selectride, which resulted, upon acidic
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spectra, [a]D values, and mass spectra) to those reported
previously.[3]
In conclusion, an efficient and stereocontrolled synthesis
of the advanced intermediate 2 en route to (ꢀ)-platensimycin
(1) has been accomplished by using (R)-(ꢀ)-carvone as an
inexpensive chiral starting material. This expedient and
flexible entry, which is applicable to both enantiomers of
platensimycin, should offer opportunities for the synthesis of
designed platensimycin analogues for chemical biology inves-
tigations.[12]
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2 with higher
Received: November 2, 2007
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Keywords: antibiotics · natural products · radicals ·
synthesis design
.
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