Total synthesis and biological evaluation of the fab-inhibitory antibiotic platencin and analogues thereof

Article abstract of DOI:10.1002/ejoc.201001281

In this article, application of the masked o-benzoquinone intramolecular Diels-Alder reaction in the total synthesis of platencin (2), a recently reported Fab inhibitory antibiotic, is described. Through intelligence gathering, the evolving strategies ult

Full text of DOI:10.1002/ejoc.201001281

FULL PAPER
DOI: 10.1002/ejoc.201001281
Total Synthesis and Biological Evaluation of the Fab-Inhibitory Antibiotic
Platencin and Analogues Thereof
Gulice Y. C. Leung,[a] Hao Li,[a] Qiao-Yan Toh,[a] Amelia M.-Y. Ng,[a] Rong Ji Sum,[a]
Julia E. Bandow,[b] and David Y.-K. Chen*[a]
Keywords: Total synthesis / Natural products / Antibiotics / Medicinal chemistry
In this article, application of the masked o-benzoquinone in-
tramolecular Diels–Alder reaction in the total synthesis of
platencin (2), a recently reported Fab inhibitory antibiotic, is
described. Through intelligence gathering, the evolving stra-
tegies ultimately culminated in three syntheses of the tricy-
clic core structure 11 of platencin (2). The influence of the
remote stereocenter(s) in the diastereoselectivity of the intra-
molecular Diels–Alder reaction was investigated, together
with a remarkable additive effect in drastically improving the
diastereoselectivity of the intramolecular Diels–Alder reac-
tion of the dienone 17. The synthetic technology developed
was further applied to the preparation of rationally designed
analogues, based on the hypothesized FabF/FabH selectivity
model. Antibacterial studies of platencin (2) and of the syn-
thesized analogues 3–9 against a panel of normal and resist-
ant strains are also reported.
geting the various stages of the fatty acid biosynthetic path-
way have been investigated as novel antibacterial agents.[5]
Recently, the discovery of platensimycin (1, Figure 1) and
platencin (2, Figure 1) by the Merck team beautifully illus-
trated the state-of-the-art technology in the identification
of novel Fab inhibitors.[6,7] In a combination of classical
high-throughput screening (HTS) of natural product ex-
tracts and the application of the RNA silencing technology
(RNAi), platensimycin (1) and platencin (2) were identified
as potent and selective inhibitor and dual inhibitor of the
fatty-acid condensing enzymes FabF and FabF/FabH,
respectively.[6a,7a] It has been suggested that the o-hy-
droxybenzoic acid moiety of platensimycin and platencin
mimics and competes with the natural β-ketoacyl (acyl-car-
rier protein) substrate, thereby terminating the elongation-
condensing step in the Fab pathway.[6a,7a] Furthermore, mo-
lecular docking studies have suggested the relevance of the
ether oxygen (Figure 1, 1, O16) in platensimycin and the
exocyclic methylene (Figure 1, 2, C15–C16) in platencin for
the observed FabF/FabH selectivity.[7b] Because these en-
zymes are highly conserved among the clinically relevant
pathogens, platensimycin (1) and platencin (2) display
broad-spectrum antibiotic activities, including activities
Introduction
The combat against infectious diseases continue to as-
sume a high priority on the global health agenda.[1] In par-
ticular, escalating reports of multidrug resistance (MDR)
threaten the eventually obsolence of existing therapies.[2]
This crisis, according to experts, could take us back to the
so-called “dark age” of the pre-antibiotic era. Several fac-
tors may contribute to the development of MDR, but it is
commonly the consequence of over-exposure to antibiotic
agents and evolutionary natural selection on the bacterial
life cycle. Over-prescribing of antibiotics, incorrect prescrip-
tion of antibiotics for viral infections, and increasing usage
of agricultural antibiotics are all sources of over-exposure.
Furthermore, patients immunocompromised through pro-
longed chemotherapy are also more susceptible to new bac-
terial infections. As such, efforts in the discovery and devel-
opment of antibiotics with novel mechanisms of action
must continue in order to combat this unmet and recurring
medical emergency.[3]
Fatty acid biosynthesis (Fab) is an essential metabolic
process for all living organisms.[4] Indeed, inhibitors tar-
[a] Chemical Synthesis Laboratory@Biopolis, Institute of against the resistant strains MRSA (methicillin-resistant
Chemical and Engineering Sciences (ICES), Agency for Science
S. aureus) and VRE (vancomycin-resistant enterococ-
Technology and Research (A*STAR),
ci).[6a,7a] However, in vivo efficacy of platensimycin (1)
11 Biopolis Way, The Helios Block, #03-08, Singapore 138667
E-mail: david_chen@ices.a-star.edu.sg
[b] Lehrstuhl für Biologie der Mikroorganismen, Fakultät für
Biologie und Biotechnologie, Ruhr-Universität Bochum,
Universitätsstrasse 150, 44801 Bochum, Germany
Fax: +49-234-3214378
could only be achieved by continuous parenteral infusion
at high dose.[6a] The clinical utility of platensimycin (1) and
platencin (2) is therefore yet to be demonstrated with
greatly improved pharmacokinetic profile, and one such
way of achieving this is through the preparation of ration-
ally designed analogues.
E-mail: julia.bandow@rub.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001281.
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D. Y. -K. Chen et al.
FULL PAPER
and C1–C3 propanoic acid) would be expected to take place
stereoselectively, leading to the tricyclic enone 11 as a suit-
able precursor. Indeed, this stereoselective double alkylation
was first demonstrated by Nicolaou’s group in their total
synthesis of (Ϯ)-platencin (2).[9a]
Figure 1. Structures of platensimycin (1), platencin (2), and the
platencin analogues 3–9.
The promising therapeutic potentials and intriguing mo-
lecular architectures of platensimycin (1) and platencin (2)
have attracted significant interest from both the biology and
the chemistry communities, with a number of elegant syn-
theses[8,9] and rationally designed analogues[10] reported.
Here we report the evolution of our synthetic strategy that
ultimately culminated in three syntheses of platencin (2). In
conjunction with our interest in the chemical/biology in-
vestigations of platencin (2), rationally designed analogues
based on the hypothesized FabH/FabF selectivity model
were synthesized, and their antibiotic activities against se-
lected bacterial strains are reported.
Scheme 1. Retrosynthetic analysis of platencin (2) leading to the
alkenyl diphenols 18, 19 and 20. TMSE = trimethylsilylethyl, TBS
= tert-butyldimethylsilyl, IMDA = intramolecular Diels–Alder.
With tricyclic enone 11 in mind, an intramolecular
Diels–Alder reaction[11] was conceived for its construction.
Inspired by the work of Liao and co-workers in the intra-
molecular cycloaddition reactions of masked o-benzo-
quinones,[12] 6,6-dimethoxycyclohexa-2,4-dienone bearing
pendent terminal alkenes, as represented by the structures
15, 16 and 17, originating from oxidative dearomatization
of desilylated versions of the aromatic phenols 18, 19 and
20, respectively, were proposed as suitable intramolecular
Results and Discussion
Retrosynthetic Analysis
While the chemical structure of platencin (2) has inspired Diels–Alder precursors. In order to access the targeted tri-
a plethora of innovative and contrasting approaches from cycle 11 stereoselectively through the proposed intramolec-
the synthetic community,[9] detachment of the aromatic do- ular Diels–Alder reaction, we envisaged the application of
main (10) at the amide bond linkage, as shown in Scheme 1, remote stereocontrol, in which the stereochemical infor-
has been widely accepted as the opening retrosynthetic ma- mation residing in the acyclic alkenyl side chain (C5 in 15,
neuver. Further retrosynthetic disassembly of platencin (2) C5,C7 in 16 and C7 in 17) would be expected to translate to
was achieved through the recognition of the inherent facial the cycloaddition adduct through a well-ordered transition
bias exhibited by its rigid cage structure, in which the se- state (15, 16 or 17). Through intelligence gathering, this
quential introduction of the two side chains (C17 methyl generalized synthetic plan ultimately culminated in three
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Total Synthesis and Biological Evaluation of Platencin
syntheses of the tricyclic enone 11, as discussed in the fol-
lowing sections and illustrated in Schemes 2, 3, 4, 5 and 6,
below.
First-Generation Synthesis of the Tricyclic Enone 11
We began our investigation into the intramolecular
Diels–Alder reaction of substrate 15 and the stereochemical
outcome of this process, influenced by its C5 hydroxy sub-
stituent (platencin numbering), as shown in Scheme 2. The
preparation of the intramolecular Diels–Alder precursor 15
commenced with a two-carbon homologation of the alde-
hyde 21[13] [(MeO)2P(O)CH2CO2Me], followed by catalytic
hydrogenation (H2, cat. Pd-C) and Dibal-H reduction of
the resulting methyl ester 23 to afford the aldehyde 24 in
60% overall yield for the three steps. Treatment of the alde-
hyde 24 with allylmagnesium bromide with subsequent desi-
lylation (TBAF) provided the phenol 26 (70% overall yield
from 24), ready for oxidative dearomatization and the pro-
posed intramolecular Diels–Alder reaction. In this instance,
oxidative dearomatization of the phenol 26 through the ac-
tion of PhI(OAc)2 in MeOH, by the protocol developed by
Liao and co-workers,[12] smoothly delivered the dimethoxy
cyclohexadienone 15 as a single detectable product. This
species proved stable to aqueous workup and was subjected
to thermal conditions after solvent exchange (MeOH to tol-
uene), to furnish the intramolecular Diels–Alder products
12a and 12b as a separable mixture of two diastereoisomers
1
(dr ≈ 1:2.5 by H NMR analysis) in 64% combined yield.
The diastereoisomeric relationship between 12a and 12b
was corroborated through oxidation of its secondary hy-
droxy group, either as a diastereoisomeric mixture or iso-
merically pure material, to deliver a single diketone (12c,
87% yield, see the Supporting Information). Furthermore,
the structure of the Diels–Alder product 12b (and therefore
of 12a) was indirectly validated through X-ray crystallo-
graphic analysis of a later intermediate (29a, Figure 3). The
preferential formation of the Diels–Alder product 12b over
12a could be interpreted on the basis of chair-like transition
Scheme 2. First-generation synthesis of the enone 11. Reagents and
conditions: a) trimethylphosphonoacetate (1.2 equiv.), LiBr
(4.0 equiv.), Et3N (2.0 equiv.), THF, 23 °C, 5 h, 70%; b) Pd-C
(0.25 equiv.), H2, MeOH, 23 °C, 30 min, 90%; c) Dibal-H (1.0 m in
toluene, 1.0 equiv.), CH2Cl2, –78 °C, 1 h, 96%; d) allylmagnesium
bromide (1.0 m in THF, 1.2 equiv.), THF, –78 °C, 2 h, 81%;
state models as illustrated in Figure 2, in which the transi- e) TBAF (1.0 m in THF, 1.1 equiv.), THF, 23 °C, 2 h, 87%;
f) PhI(OAc)2 (1.1 equiv.), KHCO3 (2.0 equiv.), MeOH, 0 Ǟ 23 °C,
tion state I would be energetically disfavoured due to its
30 min; then toluene, reflux, 4 h, 64% (ca. 2.5:1 mixture of dia-
axially positioned C5 hydroxy group exhibiting steric and
stereoisomers by 1H NMR); g) Pd-C (0.25 equiv.), H2, MeOH,
23 °C, 30 min, 89%; h) SmI2 (0.1 m in THF, 4.0 equiv.), THF/
electrostatic repulsion with the dimethyl acetal moiety. The
conformation of the newly formed six-membered ring bear-
ing the C5 hydroxy group, as depicted in the X-ray crystal-
lographic structure of 29a (Figure 3) derived from the
major Diels–Alder product 12b, also supports the hypothe-
sized transition state II. The modest level of diastereoselec-
MeOH (20:1), 23 °C, 30 min, 95%; i) MeMgBr (1.0 m in THF,
2.2 equiv.), THF, –78 °C, 2 h, 86% (ca. 1:1 mixture of diastereoiso-
mers by 1H NMR); j) DMP (1.0 equiv.), NaHCO3 (1.2 equiv.),
CH2Cl2, 23 °C, 2 h, 85%; k) TMSI (2.0 equiv.), HMDS (3.0 equiv.),
CH2Cl2, 0 Ǟ 23 °C, 6 h; then Pd(OAc)2 (1.0 equiv.), CH3CN,
23 °C, 5 h, 32: 64%, 31: 35%; l) TBAF (1.0 m in THF, 1.1 equiv.),
tivity in favour of 12b is probably due to the C5 hydroxy THF, 23 °C, 2 h, 98%; m) Martin’s sulfurane (2.0 equiv.), CH2Cl2,
23 °C, 2 h, 90%. Dibal-H = diisobutylaluminium hydride, TBAF
directing group being positioned four carbons away from
=
tetra-n-butylammonium fluoride, DMP
=
Dess–Martin
the dimethoxy acetal moiety, the steric and electrostatic re-
pulsion therefore not being severe enough to induce a
greater energetic bias between I and II.
periodinane, TMS = trimethylsilyl, HMDS = hexamethyldisilazane.
Although the stereochemical outcome of this intramolec- merically enriched alcohol 15 were employed, the poor dia-
ular Diels–Alder reaction proved inconsequential in the ra- stereoselection associated with the intramolecular Diels–Al-
cemic synthesis of the enone 11, it has an important impli- der process would lead to significant reduction in the op-
cation in the asymmetric setting. In this context, if enantio- tical purity of the ensuing intermediates upon removal of
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D. Y. -K. Chen et al.
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Figure 2. Proposed transition state structures I and II leading to the Diels–Alder products 12a and 12b, respectively.
would not be readily amenable in an asymmetric setting.
Secondly, the late-stage introduction of the enone function-
ality by the Saegusa protocol[16] (30 to 31 and 32) also suf-
fered from poor regioselectivity in the initial TMS enol
ether formation from ketone 30. With these shortcomings
in mind, a second-generation strategy was conceived and
successfully executed as shown in Scheme 3. Firstly, to im-
prove the stereoselectivity of the intramolecular Diels–
Alder reaction, we hypothesized that relocation of the
stereocentre to closer proximity in the intramolecular
Diels–Alder transition state should provide greater ener-
getic difference between the competing diastereoisomeric
reaction pathways. Furthermore, the presence of methyl
(C5) and hydroxy (C7) substituents on the alkenyl side chain
should serve as handles for the late-stage, regioselective in-
troduction of the C6–C7 enone moiety.
Figure 3. X-ray-derived ORTEP diagram of the diol 29a with ther-
mal ellipsoids shown at the 50% probability level.[14]
the C5 hydroxy chiral centre. At this point, we arbitrarily
chose the tricyclic compound 12b, and its advancement to
the targeted enone 11 was pursued in earnest. Hydrogena-
tion of the alkene 12b (H2, Pd-C) and removal of the di-
methyl acetal (SmI2)[15] in compound 27 afforded the hy-
droxy ketone 28 in 85% yield over the two steps. Grignard
addition of a methyl group at ketone 28 resulted in the diol
29, inconsequentially as an epimeric mixture at the C15 car-
The synthesis of the intramolecular Diels–Alder precur-
sor 16, bearing two neighbouring stereocentres, thus began
with an l-proline-mediated aldol[18] reaction between the
aromatic aldehyde 21 and propionaldehyde to give the β-
hydroxy aldehyde 34 as a single diastereoisomer in 83%
1
yield and Ͼ90% ee (determined by H NMR analysis of a
1
binol centre [86% yield, ca. 1:1 by H NMR spectroscopy].
Mosher ester derivative of 34; see the Supporting Infor-
mation). Two-carbon homologation of the aldehyde 34
[(MeO)2P(O)CH2CO2Me, 35], followed by silylation
(TBSOTf), afforded the enoate 36 in 84% yield over the two
steps. Dibal-H reduction of the enoate 36 afforded the al-
lylic alcohol 37 (86% yield), which was subjected to cata-
lytic hydrogenation in the presence of PtO2 (99% yield) to
give the primary alcohol 38. Dehydration of 38 through its
selenide derivative[19] (o-NO2C6H4SeCN, nBu3P; then
mCPBA, 97% yield) took place with concomitant removal
of the phenolic TBS ether, and subsequent desilylation of
the resulting TBS ether 19 furnished the hydroxy phenol 39
ready for the intramolecular Diels–Alder reaction. Under
the previously established conditions for oxidative dearo-
matization [PhI(OAc)2, MeOH], the phenol 39 was
smoothly converted into the dienone 16 and subsequently
subjected under thermal conditions (toluene, reflux) to af-
ford a separable mixture of the intramolecular Diels–Alder
products 13a and 13b in 69% yield over the two steps (13a/
13b ≈ 1:3). The diastereoisomeric relationship between 13a
and 13b was corroborated by hydrogenation, followed by
dehydrative elimination of the C7 secondary hydroxy group,
to deliver the enantiomeric keto olefins 41 and ent-41 (see
X-ray analysis of the isomer 29a [m.p. 164–167 °C (EtOAc)]
confirmed its structure (Figure 3).[14] Compound 29 was
subjected to DMP conditions to give the keto carbinol 30
in 85% yield.
The final steps leading to the targeted tricycle 11 re-
quired the introduction of the enone moiety (C6–C7), and
dehydration of the tertiary alcohol (C15) to generate the
exocyclic olefin (C15–C16). The former of these two trans-
formations was accomplished under Saegusa’s condi-
tions,[16] with subjection of a nearly 1:1.8 regioisomeric mix-
ture of TMS silyl enol ethers derived from ketone 30
(TMSI, HMDS) to Pd(OAc)2 to give a separable mixture
of the two regioisomeric enones 31 and 32 in 99% com-
bined yield (31/32 ca. 1:1.8). Removal of the TMS ether
from the major enone (32, TBAF, 98% yield), followed by
Martin’s sulfurane-mediated dehydration[17] (90% yield)
completed the synthesis of the racemic tricycle 11, the spec-
troscopic data (1H and 13C NMR) of which identically
matched those reported in the literature.[9]
Second-Generation Synthesis of the Tricyclic Enone 11
Although our first-generation strategy served to deliver the Supporting Information). Furthermore, the structure of
the targeted tricyclic enone 11, there were two major draw- the Diels–Alder product 13b (and therefore that of 13a) was
backs. Firstly, as alluded to earlier, the poor diastereoselec- indirectly validated through X-ray crystallographic analysis
tion in the intramolecular Diels–Alder reaction with the of a later intermediate (40, see Figure 5). Analogously with
substrate 15 implied that this first-generation strategy the transition state models proposed for the formation of
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Total Synthesis and Biological Evaluation of Platencin
12a and 12b [I and II, respectively], the sterically and elec-
tronically preferred transition state IV (conformation sup-
ported by X-ray structure of 40; Figure 5, below) over III
could also be conceived for the predominant formation of
the Diels–Alder product 13b (Figure 4). In contrast with the
transition states I and II, in this instance, although the ster-
ic and electrostatic pressure is more severe in III because
the C7 hydroxy group is brought into closer proximity to
the dimethyl acetal moiety, the steric repulsion between the
C5 methyl group and C7 hydroxy group experienced in both
III and IV might, however, have contributed to the modest
level of diastereoselectivity observed for the Diels–Alder re-
action of 16. Although the modest diastereoselectivity in
this second-generation intramolecular Diels–Alder reaction
had once again proved disappointing, we opted to continue
the elaboration of the intramolecular Diels–Alder product
13b (arbitrarily chosen) as outlined in Scheme 3. Catalytic
hydrogenation of the alkenyl ketone 13b gave the hydroxy
ketone 40 (Pd-C, H2, 91% yield), which was dehydrated in
the presence of Burgess’ reagent[20] to afford the alkene 41
in 67% yield. The structural identity of the hydroxy ketone
40 [m.p. 98–100 °C (hexane/EtOAc)] was confirmed by X-
ray crystallographic analysis as shown in Figure 5.[21]
Reductive removal of the dimethoxy substituents of 41
(SmI2)[15] furnished the ketone 42 (89% yield), which was
treated with methyl Grignard reagent to afford the alkenyl
carbinol 43, inconsequentially as a mixture (C15: dr ≈ 1:1),
in 73% yield. In contrast to the first-generation approach,
the regioselective introduction of the enone moiety (C6–C7)
was carried out through a dihydroxylation cleavage/aldol
condensation sequence, thereby converting the alkene 43
into the enone 33, through the intermediacy of the keto
aldehyde 44, in 80% yield over the two steps. The spectro-
scopic data (1H and 13C NMR) for enone 33 matched those
obtained in the first-generation synthesis identically,
thereby constituting a formal synthesis of the platencin core
structure 11 by interception of this late-stage intermediate.
Scheme 3. Second-generation synthesis of the enone 33. Reagents
and conditions: a) l-proline (0.1 equiv.), propionaldehyde
(5.0 equiv.), DMF, 4 °C, 48 h, 83%; b) trimethylphosphonoacetate
(1.2 equiv.), LiBr (3.8 equiv.), Et3N (2.0 equiv.), THF, 23 °C, 1 h,
99%; c) 2,6-lutidine (2.0 equiv.), TBSOTf (1.5 equiv.), CH2Cl2, –78
to 23 °C, 4 h, 85%; d) Dibal-H (1.0 m in toluene, 3.0 equiv.),
CH2Cl2, –78 °C, 2.5 h, 86%; e) PtO2 (0.2 equiv.), H2 (1 atm),
EtOAc, 23 °C, 20 h, 99%; f) o-NO2C6H4SeCN (1.4 equiv.), nBu3P
(2.0 equiv.), THF, 23 °C, 30 min; then mCPBA (2.0 equiv.),
CH2Cl2, 0 °C, 1 h; then DBU (2.0 equiv.), toluene, 80 °C, 19 h, 97%
for the three steps; g) HCl (6.0 m aq., 2.0 equiv.), MeOH, 23 °C,
1.5 h, 80%; h) PhI(OAc)2 (1.0 equiv.), KHCO3 (2.0 equiv.), MeOH,
23 °C, 1 h; then toluene, reflux, 6 h, 69% (ca. 3:1 mixture of dia-
stereoisomers by 1H NMR); i) Pd-C (0.25 equiv.), H2 (1 atm),
MeOH, 23 °C, 1 h, 91%; j) Burgess reagent (2.0 equiv.), toluene,
reflux, 19 h, 67%; k) SmI2 (0.1 m in THF, 8.0 equiv.), THF/MeOH
(20:1), 23 °C, 30 min, 89%; l) MeMgBr (1.0 m in THF, 3.0 equiv.),
Third-Generation Synthesis of the Tricyclic Enone 11
Our second-generation synthesis of tricyclic enone 11
had addressed the regioselective introduction of the C6–C7
enone moiety, but the diastereoselectivity of the intramolec-
ular Diels–Alder reaction unfortunately remained unsatis-
factory. At this juncture we turned to the intramolecular
Diels–Alder reaction of the dimethoxy-cyclohexadienone
17 (Scheme 5, a), a substrate that had previously been ex-
amined by Liao and co-workers and found to exhibit high
levels of diastereoselectivity in the intramolecular Diels–Al-
der reaction.[12] Furthermore, with an asymmetric synthesis
of the tricyclic enone 11 in mind, we envisaged that a chiral
reduction of the ketone 46 (or 47), followed by desilylation,
should deliver the alcohol 51 (precursor to the dienone 17)
in its optically active form, as shown in Schemes 4 and 5
and Table 1. The ketone 46 was thus prepared from the al-
dehyde 21[13] through the action of the Grignard reagent 45
and PCC oxidation of the intermediate alcohol 20, in 78%
1
THF, 0 °C, 17 h, 73% (ca. 1:1 mixture of diastereoisomers by H
NMR); m) OsO4 (2.5 wt.-% in tBuOH, 0.1 equiv.), NMO
(2.5 equiv.), tBuOH/acetone/H2O (1:1:1), 23 °C, 14 h; then
NaIO4 (1.5 equiv.), 23 °C, 6 h; n) NaOH (6.0 equiv.), EtOH,
23 °C, 2 h, 80% over the two steps. NMO = N-methylmorpholine
N-oxide.
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D. Y. -K. Chen et al.
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Figure 4. Proposed transition state structures III and IV leading to the Diels–Alder products 13a and 13b, respectively.
Asymmetric reduction of the ketone 46 (and 47) under
the CBS conditions[24] was examined next, and the results
are shown in Table 1. After extensive experimentation, opti-
Figure 5. X-ray-derived ORTEP diagram of the hydroxy ketone 40,
with thermal ellipsoids shown at the 50% probability level.[21]
overall yield. Alternatively, the TBDPS version of ketone
46 was directly accessible from the methyl ether 48[22]
through ortho lithiation and treatment of the resulting aryl-
lithium species with the Weinreb amide 49[23] (47, 51%
yield).
Scheme 5. Synthesis of the alkenyl ketones 14 and 55 through intra-
molecular Diels–Alder reactions. Reagents and conditions:
a) TBAF (1.0 m in THF, 1.1 equiv.), THF, 0 °C, 2 h, 99% [from (R)-
20], 92% (from 50); b) PhI(OAc)2 (1.1 equiv.), KHCO3 (2.0 equiv.),
Scheme 4. Synthesis of the racemic alcohol 20 and the ketones 46
and 47. Reagents and conditions: a) 45 (2.2 equiv.), Et2O, –10 °C,
MeOH, 0 Ǟ 23 °C, 30 min; then toluene, reflux, 4 h, 80% (ca. 15:1
1
1 h, 82%; b) PCC (1.6 equiv.), CH2Cl2, 23 °C, 16 h, 95%; c) sBuLi mixture of diastereoisomers by H NMR); c) benzyl trichloroacet-
(1.4 m in cyclohexane, 1.2 equiv.), TMEDA (1.5 equiv.), THF,
–78 °C, 45 min; then 49 (1.0 equiv.), –78 °C, 2 h, 51% (90% based
on 57% conversion). TBDPS = tert-butyldiphenylsilyl, PCC = pyr-
idinium chlorochromate, TMEDA = N,N,NЈNЈ-tetramethylethyl-
enediamine.
imidate (1.5 equiv.), TMSOTf (0.2 equiv.), CH2Cl2/hexane (1:3), 0
Ǟ 23 °C, 4 h, 76%; d) TBAF (1.0 m in THF, 3.0 equiv.), THF, 0 °C,
0.5 h, 51%; e) PhI(OAc)2 (1.1 equiv.), KHCO3 (2.0 equiv.), MeOH,
0 Ǟ 23 °C, 30 min; then toluene, reflux, 16 h, 73%. OTf = tri-
fluoromethanesulfonate, BnTCA = benzyl trichloroacetimidate.
Table 1. Asymmetric reduction of ketones 46 and 47.
Entry[a]
Solvent
Temperature [°C]
Time [h]
Yield [%][e]
Recovered [%][e]
ee[b] [%]
1
2
THF
THF
THF
THF
0
0
0
2
2
1
0.25
1
8
1
3
0.25
50: 31
50: 55
47: 54
47: 45
47: 40
47: 59
–
67
90
90
90
90
45
69
89
90
3
50: 60
4[c]
0
50: 41
5
6
7
THF
23
–78
0
0
0
50: 50
toluene
toluene
toluene
toluene
50: 57
–
50: 58
47: 23
–
–
8
(R)-20: 58
(R)-20: 99
9[c],[d]
[a] The ketone 47 was used for Entries 1–7 and the ketone 46 was used for Entries 8 and 9; BH3·SMe2 was used for Entry 1 and catechol
1
borane was used for Entries 2–9. [b] The ee value was determined by H NMR analysis of the Mosher ester derivative. [c] Alternating/
reverse addition protocol (see the Supporting Information), and reaction mixture was stirred for an additional 15 min upon completion
of addition. [d] Reaction was performed on a 15 mmol scale. [e] Yields refer to chromatographically and spectroscopically homogeneous
materials.
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Total Synthesis and Biological Evaluation of Platencin
mal conversion and enantiomeric excess were achieved Table 2. Additive effects in the intramolecular Diels–Alder reaction
of dienone 17.
through a reverse-addition protocol (see the Supporting In-
Entry[a] Additive [equiv.]
Solvent
Yield [%][b] dr[c]
formation), and the reaction was ultimately performed on
a multigram scale with excellent yield [(R)-20, 99% yield]
and optical purity (90% ee by 1H NMR analysis of the
Mosher ester derivative, Table 1, Entry 9).
1
none
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ND[d]
ND[d]
ND[d]
ND[d]
ND[d]
ND[d]
23
15:1
14:1
14:1
25:1
20:1
20:1
33:1
Ͼ50:1
17:1
20:1
42:1
31:1
31:1
Ͼ50:1
26:1
23:1
2
Ph3P (1.0)
3
4
5
6
7
8
9
10
11
12
13
TBAI/NaH (1.0)
(MeO)3B/NaH (1.0)
Ti(iPrO)4 (1.0)
(MeO)3B (1.0)
(MeO)3B/NaH (1.0)
(MeO)3B/NaH (3.0)
(iPrO)3B/NaH (1.0)
(EtO)3B/NaH (1.0)
(MeO)3B/NaH (3.0)
(MeO)3B (1.0)
(MeO)3B (3.0)
(MeO)3B (5.0)
(iPrO)3B (1.0)
With the alcohols (R)-20 and 50 in hand, their conver-
sion into the intramolecular Diels–Alder product 14 began
with the removal of the silyl ether [TBAF, 99% yield from
(R)-20 and 92% from 50], followed by PhI(OAc)2-mediated
oxidative dearomatization, to afford the intramolecular
Diels–Alder precursor 17 (Scheme 5, a). As anticipated, the
intramolecular Diels–Alder reaction of 17 proceeded with
high levels of conversion (80% yield) and diastereoselectiv-
47
65
64
toluene/THF (1:1) 62
toluene
toluene
toluene
toluene
toluene
84
85
60
63
96
ity (ca. 15:1 by 1H NMR analysis), presumably through the 14
conformationally preferred chair-like transition state VI
(over V). In contrast to the proposed transition states lead-
15
16
(EtO)3B (1.0)
[a] PhI(OAc)2 (1.1 equiv.), KHCO3 (2.0 equiv.), MeOH, 0 Ǟ 23 °C,
30 min; then toluene, reflux. [b] Yields refer to chromatographically
and spectroscopically homogeneous materials. [c] The dr value was
determined by 1H NMR analysis. [d] Not determined; TBAI =
tetra-n-butylammonium iodide.
ing to the formation of 12a/b and 13a/b (I/II and III/IV),
the energetic difference between V and VI is quite large,
thus leading to the high observed level of diastereoselectiv-
ity. Having validated the influence of the C7 (platencin num-
bering) hydroxy substituent on the diastereoselectivity as re-
ported by Liao and co-workers,[12] we hypothesized that in-
creasing the steric bulk about this hydroxy centre should
The intramolecular Diels–Alder product 14 having been
lead to a higher level of stereoinduction. This hypothesis secured in high diastereoisomeric and enantiomeric purity,
was validated by the intramolecular Diels–Alder reaction of its further elaboration to the tricyclic enone (+)-11 was pur-
the benzyl ether 54, a substrate prepared by benzylation of sued next, as outlined in Scheme 6. Hydrogenation of the
the alcohol 20 (benzyl trichloroacetimidate, TMSOTf cat., olefin moiety (C12–C13) in the tricycle 14 (H2, Pd-C) af-
76% yield) followed by silyl deprotection (TBAF, 51% forded the hydroxy ketone 56 in quantitative yield. Direct
yield) and oxidative dearomatization [PhI(OAc)2], as shown elimination of the C7 hydroxy group in 56 proved unsuc-
in part b of Scheme 5. Indeed, heating of a toluene solution cessful under a variety of reaction conditions, and so a
of the intramolecular Diels–Alder precursor 54 smoothly three-step procedure involving oxidation to the ketone
1
delivered the tricycle 55 as a single diastereoisomer (by H (PCC, 57), enol triflate formation (PhNTf2, KHMDS, 58)
NMR analysis) in 73% yield.
and reduction [Pd(PPh3)4, HCO2H] was employed to de-
Although the introduction of a sterically bulky substitu- liver the alkenyl ketone 59 in 80% yield over the three steps.
ent (e.g., Bn) at the 7-OH group served to improve the dia- The structural and stereochemical integrity of the tricyclic
stereoselectivity of the intramolecular Diels–Alder reaction, structure was also unambiguously confirmed through an X-
the installation and later removal of this protecting group ray analysis of the diketone 57 (m.p. 65–66 °C, hexane; Fig-
was less attractive in terms of the overall synthetic effi- ure 6).[25] Furthermore, the crystallinity of the diketone 57
ciency. We thus became interested in the in situ generation enabled further enantiomeric enrichment through
of a species with a temporarily increased steric environment recrystallization.
around 7-OH, which might serve a role similar to that of
Reductive cleavage of the dimethoxy substituents (C14)
a covalently attached protecting group. Along this line of in 59 was accomplished through the action of SmI2 (99%
thoughts, we hypothesized that in the presence of an oxo- yield),[15] followed by methyl Grignard addition to the re-
philic additive, a transient species derived from coordina- sulting ketone 60 to afford the tertiary alcohol 61, inconse-
tion with the 7-OH group might suffice for this purpose. quentially as a mixture of diastereoisomers (87% yield, C15:
The results of our studies are shown in Table 2. Of the addi- dr ≈ 1:1 ). Allylic oxidation of the olefin 61 through the
tives examined, alkyl borate reagents consistently produced action of Mn(OAc)3 and tBuOOH[26] smoothly furnished
high level of diastereoselectivity (Table 2, Entries 6–16). the enone 33 (80% yield) and, finally, dehydration of the
Generation of an alkoxy anion upon deprotonation of the tertiary alcohol 33 (Martin’s sulfurane,[17] 90% yield) com-
alcohol 17 with NaH was intended to form a more tightly pleted the third-generation synthesis of the tricyclic enone
bound substrate/borate complex, but the beneficial effect core of platencin. 1H and 13C NMR analysis of the tricyclic
was modest (Table 2, Entries 7–11). Overall, use of a small enone (+)-11, together with optical rotation measurements,
borate reagent [(MeO)3B] gave higher levels of stereoinduc- confirmed the diastereoisomeric and enantiomeric purity of
tion and use of five equivalents of (MeO)3B provided the the synthetic material.[9]
highest level of diastereoselectivity (Ͼ50:1 by 1H NMR
analysis), despite a slight compromise in terms of the yield from the tricyclic enone (+)-11 was accomplished in accord-
of the reaction (60%, Table 2, Entry 14). ance with the protocols developed by Nicolaou and co-
Completion of the total synthesis of (–)-platencin [(–)-2]
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189

D. Y. -K. Chen et al.
FULL PAPER
Scheme 6. Completion of the third-generation synthesis of enone
(+)-11. Reagents and conditions: a) Pd-C (0.25 equiv.), H2, MeOH,
23 °C, 30 min, 100%; b) PCC (1.6 equiv.), CH2Cl2, 23 °C, 16 h,
97%; c) PhNTf2 (1.4 equiv.), KHMDS (0.5 m in toluene,
Scheme 7. Completion of the total synthesis of (–)-platencin [(–)-
2]. Reagents and conditions: a) KHMDS (0.5 m in toluene,
1.1 equiv.), MeI (8.0 equiv.), THF/HMPA (4:1), –78 Ǟ 0 °C, 2 h,
61%; b) KHMDS (0.5 m in toluene, 4.0 equiv.), allyl iodide
(8.0 equiv.), THF/HMPA (4:1), –78 Ǟ 0 °C, 3 h, 68%; c) tert-butyl
acrylate (2.0 equiv.), tBuOK (1.0 m in tBuOH, 2.0 equiv.), THF,
23 °C, 20 min, 74% (ca. 4:1 mixture of diastereoisomers by 1H
NMR); d) LiOH (1.0 m aq., 10 equiv.), MeOH, 50 °C, 5 h; e) 10
(3.2 equiv.), HATU (3.2 equiv.), Et3N (4.2 equiv.), DMF, 23 °C,
14 h, 52% for the two steps; f) TASF (2.0 equiv.), DMF, 40 °C,
40 min, 90%. HMPA = hexamethylphosphoramide, HATU = O-
(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate, TASF = tris(dimethylamino)sulfonium difluorotrimeth-
ylsilicate.
2.3 equiv.), THF, –78
Ǟ
0 °C, 30 min; d) Pd(PPh3)2Cl2
(0.36 equiv.), nBu3N (2.7 equiv.), HCO2H (1.8 equiv.), DMF, 70 °C,
16 h, 82% for the two steps; e) SmI2 (0.1 m in THF, 4.0 equiv.),
THF/MeOH (20:1), 23 °C, 15 min, 99%; f) MeMgBr (1.0 m in
THF, 2.0 equiv.), THF, 0 Ǟ 23 °C, 30 min, 87% (ca. 1:1 mixture
of diastereoisomers by 1H NMR); g) Mn(OAc)3 (0.35 equiv.),
tBuOOH (5.0 m in decane, 4.8 equiv.), O2, EtOAc, 23 °C, 16 h,
80%; h) Martin’s sulfurane (2.0 equiv.), CH2Cl2, 23 °C, 2 h, 90%.
Tf = trifluoromethanesulfonyl, KHMDS = potassium hexameth-
ylsiliazide, DMF = N,NЈ-dimethylformamide.
Synthesis of Platencin Analogues
The utility of the intramolecular Diels–Alder reaction in
the stereoselective construction of the highly functionalized
tricyclic compound 14 having been demonstrated
(Scheme 5), its application in the synthesis of analogues for
chemical biology investigations was pursued next. As al-
luded to in the Introduction, our design of analogues was
based on the molecular docking model put forward to ex-
Figure 6. X-ray derived ORTEP diagram of the diketone 57 with
thermal ellipsoids shown at the 50% probability level.[25]
workers (Scheme 7).[9a,9b] Sequential alkylation of the enone plain the observed FabF/FabH selectivity between platensi-
(+)-11 with MeI and allyl iodide afforded the terminal al- mycin (1) and platencin (2).[7b] Therefore, in addition to the
kene 63 (41% yield for the two steps), which was further total synthesis of (–)-platencin [(–)-2], the analogues 3 and
elaborated to the acid 64, and coupling of this with aniline 4 with hydrogen-bond donor (C15 hydroxy) and acceptor
10[8k,9a,9b] (HATU,[27] 52% yield), followed by final depro- (C15 ketone) substituents were synthesized as shown in
tection (TASF,[28] 90% yield), afforded (–)-platencin [(–)-2]. Scheme 8 and Scheme 9, respectively. The synthesis of the
Alternatively, the acid 64 could be accessed through a 1,4- hydroxy analogue 3 began with a NaBH4 reduction of the
addition of the enone (+)-11 to tert-butyl acrylate (KOtBu, ketone 60 to afford a ca. 1:1 mixture of the diastereoiso-
dr ≈ 4:1 ),[9b,9i] followed by chromatographic separation of meric alcohols 68 in 95% yield. Silyl protection of the
the two diastereoisomers (66 and 67) and saponification alcohols 68 (TBSCl), followed by allylic oxidation
(LiOH) of the major isomer 67. It is interesting to note that [Mn(OAc)3, tBuOOH],[26] afforded the enones 70 in 57%
the choice of tert-butyl acrylate and a tBuOH solution of yield over the two steps. Sequential alkylation of the enones
KOtBu were extremely crucial for the success of the 1,4- 70 with MeI and allyl iodide proceeded with exclusive dia-
addition reaction.
stereoselectivity to give the terminal olefins 72 (37% yield
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Total Synthesis and Biological Evaluation of Platencin
over the two steps), which were subjected to olefin cross
metathesis with the vinyl boronate 73[29] in the presence of
the Hoveyda–Grubbs (II) catalyst[30] to afford the vinyl bo-
ronates 74 in 57% yield. Oxidation of the vinyl boronates
74 with Me3N+O– (70% yield),[31] followed by further oxi-
dation of the resulting aldehydes 75 (NaClO2), afforded the
acids 76, ready for amide bond formation to attach the aro-
matic domain. In accordance with the conditions employed
in the synthesis of (–)-platencin [(–)-2], HATU-mediated[27]
peptide coupling between the acids 76 and the aniline
10[8k,9a,9b] (54% from 75), and subsequent removal of the
silyl protecting groups from the amides 77 (TASF,[28] 64%
yield) completed the synthesis of the hydroxy analogue 3 as
a mixture of C15 epimers (ca. 1:1).
Scheme 9. Synthesis of the keto platencin analogue 4. Reagents and
conditions: a) tert-butyl acrylate (2.0 equiv.), tBuOK (1.0 m in
tBuOH, 2.0 equiv.), THF, 23 °C, 20 min (ca. 2.5:1 mixture of dia-
stereoisomers by 1H NMR); b) TBAF (1.0 m in THF, 1.0 equiv.),
THF, 23 °C, 2 h; c) DMP (1.0 equiv.), NaHCO3 (1.2 equiv.),
CH2Cl2, 23 °C, 2 h, 51% for the three steps; d) LiOH (1.0 m aq.,
13 equiv.), MeOH, 50 °C, 5 h; e) 10 (2.0 equiv.), HATU (2.3 equiv.),
Et3N (3.5 equiv.), DMF, 23 °C, 14 h, 44% for the two steps;
f) TASF (2.0 equiv.), DMF, 40 °C, 80 min, 92%.
The synthesis of the analogue 4 containing a C15 keto
moiety commenced with a 1,4-addition of the enones 71
(C15: dr ≈ 1:1) to tert-butyl acrylate, giving the tert-butyl
esters 78 as a ca. 2.5:1 mixture of C4 epimers (Scheme 9).
Desilylation of the TBS ethers 78 (TBAF), followed by oxi-
dation of the resulting secondary alcohols 79 (DMP), af-
forded a chromatographically separable mixture of the dia-
stereoisomeric ketones 80 and 81 in 51% overall yield from
the enones 71. With stereoisomerically pure tert-butyl ester
81 to hand, the final steps leading to the keto analogue
4 involved an ester hydrolysis (LiOH), followed by amide
coupling of the resulting carboxylic acid 82 with the aniline
10[8k,9a,9b] (HATU)[27] and silyl deprotection (TASF)[28] to
furnish the keto analogue 4 in 40% yield over the three
steps.
Scheme 8. Synthesis of the hydroxy platencin analogue 3. Reagents
and conditions: a) NaBH4 (1.2 equiv.), MeOH, 0 Ǟ 23 °C, 1 h,
95% (ca. 1:1 mixture of diastereoisomers by H NMR); b) TBSCl
(1.5 equiv.), imidazole (4.0 equiv.), 4-DMAP (0.1 equiv.), CH2Cl2,
0 Ǟ 23 °C, 16 h, 87%; c) Mn(OAc)3 (0.35 equiv.), tBuOOH (5.0 m
Upon revisiting our synthetic sequence leading towards
the tricyclic enone 11, we also became interested in com-
pounds bearing the C14 dimethoxy substituents for further
structural diversity. In an analogous fashion, compounds
1
in decane, 4.8 equiv.), O2, EtOAc, 23 °C, 16 h, 65%; d) KHMDS bearing hydroxy, ketone and methylene functionalities at
the C15 position, as represented by compounds 5, 6 and 7
(0.5 m in toluene, 1.3 equiv.), MeI (8.0 equiv.), THF/HMPA (4:1),
–78 Ǟ 0 °C, 2 h, 61%; e) KHMDS (0.5 m in toluene, 1.3 equiv.),
(Figure 1), were also synthesized, as shown in Schemes 10,
allyl iodide (8.0 equiv.), THF/HMPA (4:1), –78 Ǟ 0 °C, 4 h, 61%;
11 and 12, below, respectively.
f) 73 (5.0 equiv.), Hoveyda–Grubbs II cat. (0.1 equiv.), benzoqui-
none (0.1 equiv.), benzene, 70 °C, 1 h, 57%; g) Me3N+O–
(5.0 equiv.), THF, 70 °C, 3 h, 70%; h) NaClO2 (4.0 equiv.),
NaH2PO4 (7.0 equiv.), 2-methylbut-2-ene (16 equiv.), tBuOH/H2O
(1:1), 23 °C, 90 min; i) 10 (3.0 equiv.), HATU (3.0 equiv.), Et3N
(5.7 equiv.), DMF, 23 °C, 14 h, 54% for the two steps; j) TBAF
(1.0 m in THF, 9.0 equiv.), THF, 23 °C, 1 h, 64%. 4-DMAP = N,NЈ-
dimethylaminopyridine.
Synthesis of hydroxy analogues such as 5 commenced
with a NaBH4 reduction of the ketone 59 to afford a chro-
matographically separable mixture of secondary alcohols
(dr ≈ 2.5:1), the major isomer of which [C15 stereochemistry
established by X-ray crystallographic analysis of a later in-
termediate (86)] was subsequently silylated (TBSOTf) to
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191

D. Y. -K. Chen et al.
FULL PAPER
give the TBS ether 85 in 73% yield over the two steps sion from 72 to 74 (Scheme 8). Oxidation of the vinyl bor-
(Scheme 10). Allylic oxidation of the alkene 85 [Mn(OAc)3, onate 89 with Me3N+O– (100% yield)[31] and further oxi-
tBuOOH,[26] 53% yield] afforded the enone 86 {[m.p. 86– dation of the resulting aldehyde (90) with NaClO2 delivered
88 °C (hexane)], the structure was confirmed by X-ray crys- the acid 91, which was coupled with the aniline 10[8k,9a,9b]
tallographic analysis, see Figure 7},[32] and conversion of (HATU)[27] and desilylated (TASF)[28] to complete the di-
this compound into the terminal olefin 88 was by the pre- methoxy hydroxy analogue 5 (39% yield from aldehyde 90).
viously described, sequential stereoselective alkylation with
MeI and allyl iodide in the presence of KHMDS and
HMPA (38% yield for the two steps). The terminal alkene
88 was further homologated to the vinyl boronate 89 in a
fashion analogous to that described earlier for the conver-
Figure 7. X-ray derived ORTEP diagram of the diketone 86 with
thermal ellipsoids shown at the 50% probability level.[32]
As shown in Scheme 11, the synthesis of the dimethoxy
ketone analogue 6 took advantage of the dimethoxy ketone
59, and its conversion into the enone 93 was carried out by
Scheme 10. Synthesis of the dimethoxy hydroxy platencin analogue
5. Reagents and conditions: a) NaBH4 (1.6 equiv.), MeOH, 0 °C,
1 h, 82% (ca. 2.5:1 mixture of diastereoisomers by 1H NMR);
b) TBSOTf (1.6 equiv.), 2,6-lutidine (2.0 equiv.), CH2Cl2, –78 °C,
2 h, 89%; c) Mn(OAc)3 (0.35 equiv.), tBuOOH (5.0 m in decane,
4.8 equiv.), O2, EtOAc, 23 °C, 15 h, 53%; d) KHMDS (0.5 m in tol-
uene, 1.2 equiv.), MeI (8.0 equiv.), THF/HMPA (4:1), –78 Ǟ 0 °C,
2 h, 80% (ca. 5.5:1 mixture of diastereoisomers by 1H NMR);
e) KHMDS (0.5 m in toluene, 1.2 equiv.), allyl iodide (8.0 equiv.),
THF/HMPA (4:1), –78 Ǟ 0 °C, 4 h, 48% (ca. 4:1 mixture of dia-
Scheme 11. Synthesis of the dimethoxy ketone platencin analogue
6. Reagents and conditions: a) Mn(OAc)3 (0.35 equiv.), tBuOOH
(5.0 m in decane, 4.8 equiv.), O2, EtOAc, 23 °C, 16 h, 73%;
b) KHMDS (0.5 m in toluene, 1.2 equiv.), MeI (8.0 equiv.), THF/
HMPA (4:1), –78 Ǟ 0 °C, 2 h, 72%; c) KHMDS (0.5 m in toluene,
1.2 equiv.), allyl iodide (8.0 equiv.), THF/HMPA (4:1), –78 Ǟ 0 °C,
1
4 h, 56% (ca. 4:1 mixture of diastereoisomers by H NMR); d) 73
1
stereoisomers by H NMR); f) 73 (5.0 equiv.), Hoveyda–Grubbs II
(5.0 equiv.), Hoveyda–Grubbs II cat. (0.1 equiv.), benzoquinone
(0.1 equiv.), benzene, 70 °C, 1 h, 35%; e) Me3N+O– (5.0 equiv.),
THF, 70 °C, 3 h, 74%; f) NaClO2 (3.0 equiv.), NaH2PO4
(5.0 equiv.), 2-methylbut-2-ene (11 equiv.), tBuOH/H2O (1:1),
cat. (0.1 equiv.), benzoquinone (0.1 equiv.), benzene, 70 °C, 1 h,
35%; g) Me3N+O– (5.0 equiv.), THF, 70 °C, 18 h, 100%; h) NaClO2
(3.0 equiv.), NaH2PO4 (5.0 equiv.), 2-methylbut-2-ene (11 equiv.),
tBuOH/H2O (1:1), 23 °C, 90 min; i) 10 (3.0 equiv.), HATU 23 °C, 90 min; g) 10 (3.0 equiv.), HATU (3.0 equiv.), Et3N
(3.0 equiv.), Et3N (4.0 equiv.), DMF, 23 °C, 14 h, 44% for the two
steps; j) TBAF (1.0 m in THF, 8.0 equiv.), THF, 23 °C, 1 h, 88%.
(4.0 equiv.), DMF, 23 °C, 14 h, 60% for the two steps; h) TASF
(2.0 equiv.), DMF, 40 °C, 80 min, 81%.
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Total Synthesis and Biological Evaluation of Platencin
the Mn(OAc)3/tBuOOH protocol[26] in 73% yield. Sequen- (Me3N+O– then NaClO2)[31] of the intermediate vinyl bor-
tial alkylation of the enone 93 with MeI and allyl iodide led onate 104 proceeded uneventfully to deliver the acid 106,
to an inseparable pair of diastereoisomers epimeric at C4 amide coupling of which (HATU)[27] with the aniline 10
(95, dr ≈ 4:1 ), which were further elaborated to the acid 98 and final deprotection (TASF)[28] gave the dimethoxy meth-
through the cross-metathesis and double oxidation se- ylene analogue 7 in 30% yield from the aldehyde 105.
quence. Amide bond coupling between the acid 98 and the
As the final additions to our collection of platencin ana-
aniline 10[8k,9a,9b] (HATU)[27] and final deprotection logues, the reverse alkylation analogue 8 [C4-epi-platencin,
(TASF)[28] then completed the dimethoxy ketone analogue C4-epi-(–)-2] and the α,β-unsaturated amide 9 were also
6 in 49% yield from 97 (dr ≈ 4:1 ).
synthesized, as shown in Scheme 13. Hydrolysis (LiOH) of
The synthesis of the dimethoxy methylene analogue 7 be- the previously described diastereoisomeric tert-butyl ester
gan with a Wittig olefination of the ketone 59 (Ph3P=CH2, 66 (Scheme 7), followed by amide coupling with the aniline
100), followed by allylic oxidation [Mn(OAc)3, 10[8k,9a,9b] (HATU)[27] and desilylation (TASF),[28] furnished
tBuOOH],[26] to afford the enone 101 in 64% yield over the C4-epi-platencin (8) in 48% yield over the three steps
two steps (Scheme 12). The double alkylation product 103 (Scheme 13, a).
was obtained as a single diastereoisomer under the pre-
viously described conditions (46% yield over the two steps
from the enone 101). Olefin cross-metathesis (73,[29] Hov-
eyda–Grubbs II catalyst)[30] and subsequent oxidations
Scheme 13. Syntheses of the reverse-alkylation platencin analogue
8 and the α,β-unsaturated amide analogue 9. Reagents and condi-
tions: a) LiOH (1.0 m aq., 10 equiv.), MeOH, 50 °C, 5 h; b) 10
(2.2 equiv.), HATU (2.2 equiv.), Et3N (3.2 equiv.), DMF, 23 °C,
14 h, 57% for the two steps; c) TASF (1.4 equiv.), 40 °C, 80 min,
85%; d) acrylic acid (1.0 equiv.), Et3N (1.3 equiv.), HOBt
(1.0 equiv.), EDAC (1.0 equiv.), DMF, 23 °C, 16 h, 94%; e) 110
Scheme 12. Synthesis of the dimethoxy methylene platencin ana-
(1.3 equiv.), Hoveyda–Grubbs II cat. (0.05 equiv.), CH2Cl2, 50 °C,
logue 7. Reagents and conditions: a) (bromomethyl)triphenylphos-
phonium bromide (8.0 equiv.), tBuONa (8.0 equiv.), Et2O, 45 °C,
12 h, 42%; f) TASF (2.0 equiv.), DMF, 40 °C, 80 min, 95%. HOBt
=
N-hydroxybenzotriazole, EDAC
= 1-ethyl-3-(3-dimethylami-
2 h, 80%; b) Mn(OAc)3 (0.35 equiv.), tBuOOH (5.0 m in decane,
4.8 equiv.), O2, EtOAc, 23 °C, 15 h, 80%; c) KHMDS (0.5 m in tol-
uene, 1.2 equiv.), MeI (8.0 equiv.), THF/HMPA (4:1), –78 Ǟ 0 °C,
2 h, 76%; d) KHMDS (0.5 m in toluene, 1.2 equiv.), allyl iodide
(8.0 equiv.), THF/HMPA (4:1), –78 Ǟ 0 °C, 4 h, 60%; e) 73
(5.0 equiv.), Hoveyda–Grubbs II cat. (0.1 equiv.), benzoquinone
(0.1 equiv.), benzene, 70 °C, 1 h, 65%; f) Me3N+O– (5.0 equiv.),
THF, 70 °C, 3 h, 60%; g) NaClO2 (3.8 equiv.), NaH2PO4
(7.0 equiv.), 2-methylbut-2-ene (15 equiv.), tBuOH/H2O (1:1),
23 °C, 90 min; h) 10 (3.0 equiv.), HATU (3.0 equiv.), Et3N
(5.0 equiv.), DMF, 23 °C, 14 h, 63% for the two steps; i) TASF
(2.0 equiv.), DMF, 40 °C, 80 min, 47%.
nopropyl)carbodiimide.
Olefin cross-metathesis with the terminal alkene 63 and
the acrylamide 110 in the presence of the Hoveyda–
Grubbs II catalyst[30] smoothly delivered the α,β-unsatu-
rated amide 111 as a single geometric isomer, which was
desilylated (TASF)[28] to give the analogue 9 in 40% overall
yield for the two steps (Scheme 13, b).
Eur. J. Org. Chem. 2011, 183–196
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193

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Table 3. Antibacterial studies of (–)-platencin [(–)-2] and its analogues 3–9.
Entry
MIC[a] [μg/mL]
S. aureus COL
(MRSA)
S. aureus Mu50 S. aureus
B. subtilis
S. aureus
SG511
E. coli
W3110
P. aeruginosa
PA01
(VISA)
ATCC43300 (MRSA) 168
1
2
3
4
5
6
7
8
(–)-2
0.1
Ͼ128
Ͼ128
16
8
4
0.25
Ͼ128
Ͼ128
32
16
8
1
0.25
Ͼ128
Ͼ128
64
16
8
0.5
0.25
Ͼ128
Ͼ128
Ͼ128
8
32
1
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
3
4
5
6
7
8
9
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
2
8
1
Ͼ128
Ͼ128
Ͼ128
Ͼ128
Ͼ128
[a] Minimal inhibitory concentrations (MICs) were determined by a standard microtitre plate assay. Compound stock solutions
(10 mgmL–1) were prepared in DMSO. Serial dilutions of compounds in Luria Bertani (LB) broth were inoculated with 5ϫ105 cellsmL–1
and incubated for 18 h at 37 °C.
Antibacterial Studies of (–)-Platencin [(–)-2] and the
Platencin Analogues 3–9
tated the preparation of rationally designed analogues in-
corporating hydrogen bond donating, accepting and lipo-
philic substituents at C15, as demonstrated in the synthesis
of the platencin analogues 3–9. The highly flexible synthetic
technology, together with preliminary SAR insights, should
enable further chemical biology investigations of this fasci-
nating class of compounds.
The synthesized compounds were tested against a panel
of bacterial strains, including S. aureus COL (MRSA),
S. aureus Mu50 (VISA), S. aureus ATCC43300 (MRSA),
B. subtilis 168, S. aureus SG511, E. coli W3110 and P. aeru-
ginosa PA01 with synthetic (–)-platencin [(–)-2] as positive
control, and the results are summarized in Table 3. The hy-
droxy analogue 3 (Table 3, Entry 2) and the ketone ana-
logue 4 (Table 3, Entry 3) of platencin showed complete loss
of antibacterial activities against both normal and resistant
strains. The dimethoxy analogues 5–7 (Table 3, Entries 4–6)
also showed significant reduction in antibacterial activities,
but these compounds seem to show selectivity toward the
resistant strains S. aureus COL (MRSA), S. aureus Mu50
(VISA), S. aureus ATCC43300 (MRSA) and S. aureus
SG511. Much to our surprise, the reverse alkylation ana-
logue 8 also showed modest levels of antibiotic activity,
whereas the α,β-unsaturated amide 9 showed complete loss
of antibacterial activities. Clearly, further studies are needed
in order to seek structural simplification and diversification
in parallel with improvement of platencin’s antibiotic prop-
erty. Work in this area, together with the FabF/FabH selec-
tivity of analogues 3–9, is currently underway and the re-
sults will be reported in due course.
Supporting Information (see also the footnote on the first page of
this article): General information for the Experimental Section, ex-
perimental procedures and compound characterization, materials
and methods for antibacterial assays, and 1H and 13C NMR spectra
for all compounds.
Acknowledgments
We thank Ms. Sanny G. Ing (ICES-CSL), Mr. Kelvin S.-L. Chan
(ICES-CSL), and Ms. Catherine Lau (ICES-CSL) for their assist-
ance, Dr. Aitipamula Srinivasulu (ICES) and Ms. Chia Sze Chen
(ICES) for X-ray crystallographic analysis, and Ms. Doris Tan
(ICES) for high-resolution mass spectrometric (HRMS) assistance.
Financial support for this work was provided by A*STAR, Singa-
pore.
[1] a) G. S. Omenn, Proc. Natl. Acad. Sci. USA 2010, 107, 1702–
1709; b) K. E. Jones, N. G. Patel, M. A. Levy, A. Storeygard,
D. Balk, J. L. Gittleman, P. Daszak, Nature 2008, 451, 990–
993.
[2] a) J. Davies, Antibiotic Resistance: Origins, Evolution, Selection
and Spread, Wiley, 1997. For a series of reviews on antibiotic
resistance, see: ; b) C. T. Walsh, G. Wright, Chem. Rev. 2005,
105, 391–774; c) K. M. Overbye, J. F. Barrett, Drug Disc. Today
2005, 10, 45–52.
[3] a) M. A. Fischbach, C. T. Walsh, Science 2009, 325, 1089–
1093; b) A. L. Demain, S. Sanchez, J. Antibiot. 2009, 62, 5–
16; c) M. Gualtieri, F. Baneres-Roquet, P. Villain-Guillot, M.
Pugniere, J.-P. Leonetti, Curr. Med. Chem. 2009, 16, 390–393;
d) D. J. Payne, M. N. Gwynn, D. J. Holmes, D. L. Pompliano,
Nat. Rev. Drug Discovery 2007, 6, 29–40.
[4] a) S. W. White, J. Zheng, Y.-M. Zhang, C. O. Rock, Annu. Rev.
Biochem. 2005, 74, 791–831; b) J. W. Campbell, J. E.
Cronan Jr., Annu. Rev. Microbiol. 2001, 55, 305–332; c) R. J.
Heath, S. W. White, C. O. Rock, Prog. Lipid. Res. 2001, 40,
467–497; d) R. J. Heath, C. O. Rock, Curr. Opin. Invest. Drugs
2004, 5, 146–153; e) Y.-M. Zhang, Y.-J. Lu, C. O. Rock, Lipids
2004, 39, 1055–1060; f) H. T. Wright, K. A. Reynolds, Curr.
Opin. Microbiol. 2007, 10, 447–453.
Conclusions
In summary, the total synthesis of the recently disclosed,
broad-spectrum fatty-acid synthase inhibitory antibiotic
(–)-platencin [(–)-2] has been accomplished. The synthetic
strategy featured the application of the masked o-benzoqui-
nones intramolecular Diels–Alder reaction, and highlighted
the directing effect of remote stereocentres in the alkenyl
side chain, as illustrated in substrates 15, 16, and 17, in the
observed diastereoselectivity of the intramolecular Diels–
Alder reaction. Furthermore, the use of borate reagent as
an additive led to dramatic improvements in the diastereo-
selectivity of the Diels–Alder reaction of substrate 17. The
developed synthetic strategy, together with the readily ac-
cessible and highly functionalized tricyclic system 14, facili-
194
www.eurjoc.org
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Eur. J. Org. Chem. 2011, 183–196

Total Synthesis and Biological Evaluation of Platencin
[5]
A. K. Ghosh, K. Xi, J. Org. Chem. 2009, 74, 1163–1170; l) S. Y.
Yun, J.-C. Zheng, D. Lee, J. Am. Chem. Soc. 2009, 131, 8413–
8415; m) K. C. Nicolaou, A. Li, S. P. Ellery, D. J. Edmonds,
Angew. Chem. 2009, 121, 4411–4413; Angew. Chem. Int. Ed.
2009, 48, 6293–6295; n) N. A. McGrath, E. S. Bartlett, S. Sitti-
han, J. T. Njardarson, Angew. Chem. 2009, 121, 8695–8698; An-
gew. Chem. Int. Ed. 2009, 48, 8543–8546; o) K. C. Nicolaou,
A. Li, D. J. Edmonds, G. S. Tria, S. P. Ellery, J. Am. Chem. Soc.
2009, 131, 16905–16918; p) S. Xing, W. Pan, C. Liu, J. Ren, Z.
Wang, Angew. Chem. 2010, 122, 3283–3286; Angew. Chem. Int.
Ed. 2010, 49, 3215–3218; q) K. Tiefenbacher, L. Troendlin, J.
Mulzer, A. Pfaltz, Tetrahedron 2010, 66, 6508–6513. For studies
directed toward the platensimycin core, see: r) A. K. Ghosh,
K. Xi, Org. Lett. 2007, 9, 4013–4016; s) K. P. Kaliappan, V.
Ravikumar, Org. Lett. 2007, 9, 2417–2419. For reviews on the
synthesis of platensimycin and related antibiotics, see: t) K. C.
Nicolaou, J. S. Chen, D. J. Edmonds, A. A. Estrada, Angew.
Chem. 2009, 121, 670–732; Angew. Chem. Int. Ed. 2009, 48,
660–719; u) K. Tiefenbacher, J. Mulzer, Angew. Chem. 2008,
120, 2582–2590; Angew. Chem. Int. Ed. 2008, 47, 2548–2555;
v) K. Palanichamy, K. P. Kaliappan, Chem. Asian J. 2010, 5,
668–703.
a) K. C. Nicolaou, G. S. Tria, D. J. Edmonds, Angew. Chem.
2008, 120, 1804–1807; Angew. Chem. Int. Ed. 2008, 47, 1780–
1783; b) K. C. Nicolaou, G. S. Tria, D. J. Edmonds, M. Kar, J.
Am. Chem. Soc. 2009, 131, 15909–15917; c) J. Hayashida, V. H.
Rawal, Angew. Chem. 2008, 120, 4445–4448; Angew. Chem. Int.
Ed. 2008, 47, 4373–4376; d) K. Tiefenbacher, J. Mulzer, Angew.
Chem. 2008, 120, 6294–6295; Angew. Chem. Int. Ed. 2008, 47,
6199–6200; e) S. Y. Yun, J.-C. Zheng, D. Lee, Angew. Chem.
2008, 120, 6297–6299; Angew. Chem. Int. Ed. 2008, 47, 6201–
6203; f) D. C. J. Waalboer, M. C. Schaapman, F. L. Van Delft,
F. P. J. T. Rutjes, Angew. Chem. 2008, 120, 6678–6680; Angew.
Chem. Int. Ed. 2008, 47, 6576–6578; g) K. C. Nicolaou, Q.-Y.
Toh, D. Y.-K. Chen, J. Am. Chem. Soc. 2008, 130, 11292–
11293; h) K. A. B. Austin, M. G. Banwell, A. C. Willis, Org.
Lett. 2008, 10, 4465–4468; i) K. Tiefenbacher, J. Mulzer, J. Org.
Chem. 2009, 74, 2937–2941; j) G. N. Varseev, M. E. Maier, An-
gew. Chem. 2009, 121, 3739–3742; Angew. Chem. Int. Ed. 2009,
48, 3685–3688; k) A. K. Ghosh, K. Xi, Angew. Chem. 2009,
121, 5476–5479; Angew. Chem. Int. Ed. 2009, 48, 5372–5375.
For a review on the synthesis of platencin, see: l) K. Palanich-
amy, K. P. Kaliappan, Chem. Asian J. 2010, 5, 668–703.
a) K. Young, H. Jayasuriya, J. G. Ondeyka, K. Herath, C.
Zhang, S. Kodali, A. Galgoci, R. Painter, V. Brown-Driver, R.
Yamamoto, L. L. Silver, Y. Zheng, J. I. Ventura, J. Sigmund, S.
Ha, A. Basilio, F. Vicente, J. F. Tormo, F. Pelaez, P. Youngman,
D. Cully, J. F. Barrett, D. Schmatz, S. B. Singh, J. Wang, Anti-
microb. Agents Chemother. 2006, 50, 519–526; b) R. J. Heath,
Y. T. Yu, M. A. Shapiro, E. Olson, C. O. Rock, J. Biol. Chem.
1998, 273, 30316–30320; c) A. Banerjee, E. Dubnau, A. Quem-
ard, V. Balasubramanian, K. S. Um, T. Wilson, D. Collins, G.
de Lisle, W. R. Jacobs Jr., Science 1994, 263, 227–230; d) C.
Baldock, J. B. Rafferty, S. E. Sedelnikova, P. J. Baker, A. R.
Stuitje, A. R. Slabas, T. R. Hawkes, D. W. Rice, Science 1999,
274, 2107–2110; e) D. A. Heerding, G. Chan, W. E. DeWolf,
A. P. Fosberry, C. A. Janson, D. D. Jaworski, E. McManus,
W. H. Miller, T. D. Moore, D. J. Payne, X. Qiu, S. F. Ritten-
house, C. Slater-Radosti, W. Smith, D. T. Takata, K. S. Vaidya,
C. C. Yuan, W. F. Huffman, Bioorg. Med. Chem. Lett. 2001,
11, 2061–2065; f) M. A. Seefeld, W. H. Miller, K. A. New-
lander, W. J. Burgess, W. E. DeWolf, Jr., P. A. Elkins, M. A.
Head, D. R. Jakas, C. A. Janson, P. M. Keller, P. J. Manley,
T. D. Moore, D. J. Paine, S. Pearson, B. J. Polizzi, X. Qiu, S. F.
Rittenhouse, I. N. Uzinskas, N. G. Wallis, W. F. Huffman, J.
Med. Chem. 2003, 46, 1627–1635; g) A. C. Price, K. H. Choi,
R. J. Heath, Z. Li, S. W. White, C. O. Rock, J. Biol. Chem.
2001, 276, 6551–6559; h) C. Freiberg, N. A. Brunner, G.
Schiffer, T. Lampe, J. Pohlmann, M. Brands, M. Raabe, D.
Häbich, K. Ziegelbauer, J. Biol. Chem. 2004, 279, 26066–
26073.
[9]
[6]
For isolation of platensimycin, see: a) J. Wang, S. M. Soisson,
K. Young, W. Shoop, S. Kodali, A. Galgoci, R. Painter, G.
Parthasarathy, Y. S. Tang, R. Cummings, S. Ha, K. Dorso, M.
Motyl, H. Jayasuriya, J. Ondeyka, K. Herath, C. Zhang, L.
Hernandez, J. Allocco, A. Basilio, J. R. Tormo, O. Genilloud,
F. Vicente, F. Pelaez, L. Colwell, S. H. Lee, B. Michael, T. Fel-
cetto, C. Gill, L. L. Silver, J. D. Hermes, K. Bartizal, J. Barrett,
D. Schmatz, J. W. Becker, D. Cully, S. B. Singh, Nature 2006,
441, 358–361; b) S. B. Singh, H. Jayasuriya, J. G. Ondeyka,
K. B. Herath, C. Zhang, D. L. Zink, N. N. Tsou, R. G. Ball,
A. Basilio, O. Genilloud, M. T. Diez, F. Vicente, F. Pelaez, K.
Young, J. Wang, J. Am. Chem. Soc. 2006, 128, 11916–11920; c)
S. B. Singh, K. B. Herath, J. Wang, N. Tsou, R. G. Ball, Tetra-
hedron Lett. 2007, 48, 5429–5433; d) K. B. Herath, A. B. At-
tygalle, S. B. Singh, J. Am. Chem. Soc. 2007, 129, 15422–15423.
[10]
[7]
a) K. C. Nicolaou, T. Lister, R. M. Denton, A. Montero, D. J.
Edmonds, Angew. Chem. 2007, 119, 4796–4798; Angew. Chem.
Int. Ed. 2007, 46, 4712–4714; b) K. C. Nicolaou, Y. Tang, J.
Wang, A. F. Stepan, A. Li, A. Montero, J. Am. Chem. Soc.
2007, 129, 14850–14851; c) K. C. Nicolaou, A. F. Stepan, T.
Lister, A. Li, A. Montero, G. S. Tria, C. I. Turner, Y. Tang, J.
Wang, R. M. Denton, D. J. Edmonds, J. Am. Chem. Soc. 2008,
130, 13110–13119; d) Y.-Y. Yeung, E. J. Corey, Org. Lett. 2008,
10, 3877–3878; e) J. Wang, V. Lee, H. O. Sintim, Chem. Eur. J.
2009, 15, 2747–2750; f) H. C. Shen, F. Ding, S. B. Singh, G.
Parthasarathy, S. M. Soisson, S. N. Ha, X. Chen, S. Kodali, J.
Wang, K. Dorso, J. R. Tata, M. L. Hammond, M. MacCoss,
S. L. Colletti, Bioorg. Med. Chem. Lett. 2009, 19, 1623–1627;
g) K. P. Jang, C. H. Kim, S. W. Na, H. Kim, H. Kang, E. Lee,
Bioorg. Med. Chem. Lett. 2009, 19, 4601–4602; h) O. V. Baryk-
ina, K. L. Rossi, M. J. Rybak, B. B. Snider, Org. Lett. 2009, 11,
5334–5337; i) K. Tiefenbacher, A. Gollner, J. Mulzer, Chem.
Eur. J. 2010, 16, 9616–9622; j) D. C. J. Waalboer, S. H. A. M.
Leenders, T. Schülin-Casonato, F. L. Van Delft, F. P. J. T.
Rutjes, Chem. Eur. J. 2010, 16, 11233Ϫ11236.
For isolation of platencin, see: a) J. Wang, S. Kodali, S. H. Lee,
A. Galgoci, R. Painter, K. Dorso, F. Racine, M. Motyl, L.
Hernandez, E. Tinney, S. Colletti, K. Herath, R. Cummings,
O. Salazar, I. Gonzalez, A. Basilio, F. Vicente, O. Genilloud,
F. Pelaez, H. Jayasuriya, K. Young, D. Cully, S. B. Singh, Proc.
Natl. Acad. Sci. USA 2007, 104, 7612–7616; b) H. Jayasuriya,
K. B. Herath, C. Zhang, D. L. Zink, A. Basilio, O. Genilloud,
M. T. Diez, F. Vicente, I. Gonzalez, O. Salazar, F. Pelaez, R.
Cummings, S. Ha, J. Wang, S. B. Singh, Angew. Chem. 2007,
119, 4768–4772; Angew. Chem. Int. Ed. 2007, 46, 4684–4688.
a) K. C. Nicolaou, A. Li, D. J. Edmonds, Angew. Chem. 2006,
118, 7244–7248; Angew. Chem. Int. Ed. 2006, 45, 7086–7090;
b) K. C. Nicolaou, D. J. Edmonds, A. Li, G. S. Tria, Angew.
Chem. 2007, 119, 4016–4019; Angew. Chem. Int. Ed. 2007, 46,
3942–3945; c) Y. Zou, C.-H. Chen, C. D. Taylor, B. M. Fox-
man, B. B. Snider, Org. Lett. 2007, 9, 1825–1828; d) K. C. Nic-
olaou, Y. Tang, J. Wang, Chem. Commun. 2007, 1922–1923; e)
P. Li, J. N. Payette, H. Yamamoto, J. Am. Chem. Soc. 2007,
129, 9534–9535; f) G. Lalic, E. J. Corey, Org. Lett. 2007, 9,
4921–4923; g) K. Tiefenbacher, J. Mulzer, Angew. Chem. 2007,
119, 8220–8221; Angew. Chem. Int. Ed. 2007, 46, 8074–8075;
h) K. C. Nicolaou, D. Pappo, K. Y. Tsang, R. Gibe, D. Y.-K.
Chen, Angew. Chem. 2008, 120, 958–960; Angew. Chem. Int.
Ed. 2008, 47, 944–946; i) C. H. Kim, K. P. Jang, S. Y. Choi,
Y. K. Chung, E. Lee, Angew. Chem. 2008, 120, 4073–4075; An-
gew. Chem. Int. Ed. 2008, 47, 4009–4011; j) J.-I. Matsuo, K.
Takeuchi, H. Ishibashi, Org. Lett. 2008, 10, 4049–4052; k)
[8]
[11]
K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassilikogian-
nakis, Angew. Chem. 2002, 114, 1742–1773; Angew. Chem. Int.
Ed. 2002, 41, 1668–1698.
Y.-K. Chen, R. K. Peddinti, C.-C. Liao, Chem. Commun. 2001,
15, 1340–1341, and references cited therein.
[12]
[13]
T. Harayama, T. Sato, Y. Nakano, H. Abe, Y. Takeuchi, Het-
erocycles 2003, 59, 293–301.
Eur. J. Org. Chem. 2011, 183–196
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
195

D. Y. -K. Chen et al.
FULL PAPER
[14] CCDC-781698 contains the supplementary crystallographic
data for compound 29a. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[15] For selected reviews on the use of samarium diiodide in chemi-
cal synthesis, see: a) K. C. Nicolaou, S. P. Ellery, J. S. Chen,
Angew. Chem. 2009, 121, 7376–7301; Angew. Chem. Int. Ed.
2009, 48, 7140–7165; b) D. J. Edmonds, D. Johnston, D. J.
Procter, Chem. Rev. 2004, 104, 3371–3403; c) H. B. Kagan, Tet-
rahedron 2003, 59, 10351–10372; d) G. A. Molander, C. R.
Harris, Chem. Rev. 1996, 96, 307–338.
McLean, S. C. Kemp, N. P. Camp, R. C. D. Brown, Org. Lett.
2007, 9, 1867–1869.
E. J. Corey, C. J. Helal, Angew. Chem. 1998, 110, 2092–2118;
Angew. Chem. Int. Ed. 1998, 37, 1986–2012.
CCDC-781877 contains the supplementary crystallographic
data for compound 57. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
T. K. M. Shing, Y.-Y. Yeung, P. L. Su, Org. Lett. 2006, 8, 3149–
3151.
L. Carpino, A. El-Faham, C. A. Minor, F. Albericio, J. Chem.
Soc., Chem. Commun. 1994, 2, 201–203.
W. J. Middleton, Org. Synth Coll. Vol. 1990, 7, 528.
[24]
[25]
[26]
[27]
[28]
[16] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011–1013.
[17] a) J. C. Martin, R. J. Arhart, J. Am. Chem. Soc. 1971, 93, 4327–
4329; b) R. J. Arhart, J. C. Martin, J. Am. Chem. Soc. 1972,
94, 5003–5010.
[29] C. Morrill, R. H. Grubbs, J. Org. Chem. 2003, 68, 6031–6034.
[30] a) J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus, A. H. Hov-
eyda, J. Am. Chem. Soc. 1999, 121, 791–799; b) S. B. Garber,
J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am. Chem. Soc.
2000, 122, 8168–8179; c) For a short review on these catalysts,
see: A. H. Hoveyda, D. G. Gillingham, J. J. Van Veldhuizen, O.
Kataoka, S. B. Garber, J. S. Kingsbury, J. P. A. Harrity, Org.
Biomol. Chem. 2004, 2, 1–16.
[18] A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798–6799.
[19] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41,
1485–1486.
[20] a) G. M. Atkins Jr., E. M. Burgess, J. Am. Chem. Soc. 1968, 90,
4744–4745; b) E. M. Burgess, H. R. Penton Jr., E. A. Taylor, J.
Am. Chem. Soc. 1970, 92, 5224–5226; c) E. M. Burgess, H. R.
Penton Jr., E. A. Taylor, J. Org. Chem. 1973, 38, 26–31.
[21] CCDC-781697 contains the supplementary crystallographic
data for compound 40. This data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[31] G. W. Kabalka, H. C. Hedgecock Jr., J. Org. Chem. 1975, 40,
1776–1779.
[32] CCDC-782614 contains the supplementary crystallographic
data for compound 86. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[22] A. Stern, J. S. Swenton, J. Org. Chem. 1987, 52, 2763–2768.
[23] a) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–
3818. For the Weinreb amide 49, see: b) V. Satcharoen, N. J.
Received: September 13, 2010
Published Online: November 23, 2010
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www.eurjoc.org
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