Enantioselective Synthesis of the Platensimycin Core by Silver(I)-Promoted Cyclization of Δ6-α-Iodoketone

Article abstract of DOI:10.1002/chem.201900497

A chiral-pool-based synthesis of the platensimycin core was achieved using (S)-lactic acid as an inexpensive starting material. The cyclohexenone ring was closed in a Mukaiyama–Michael domino sequence, while the quaternary stereocenter was created by a highly stereoselective decarboxylative allylation. The spirobicyclic skeleton was constructed by a RCM reaction. A new silver(I)-promoted cyclization reaction of Δ⁶- and Δ⁷-α-iodoketones was developed and applied for the pivotal carbon–carbon bond formation. The scope and limitations of this methodology are also presented.

Full text of DOI:10.1002/chem.201900497

A Journal of
Accepted Article
Title: Enantioselective Synthesis of the Platensimycin Core by Silver(I)-
Promoted Cyclization of D6-a-Iodoketone
Authors: Filip Bihelovic, Radomir N. Saicic, Zorana Ferjancic, and
Milos Trajkovic
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To be cited as: Chem. Eur. J. 10.1002/chem.201900497
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10.1002/chem.201900497
Chemistry - A European Journal
COMMUNICATION
Enantioselective Synthesis of the Platensimycin Core by Silver(I)-
Promoted Cyclization of ∆6-α-Iodoketone
Milos Trajkovic,[a] Zorana Ferjancic,[a] Radomir N. Saicic* [a,b] and Filip Bihelovic* [a]
Abstract: A chiral pool based synthesis of the platensimycin core
was achieved using (S)-lactic acid as an inexpensive starting
material. The cyclohexenone ring was closed in a Mukaiyama-
Michael domino sequence, while the quaternary stereocenter was
created by a highly stereoselective decarboxylative allylation. The
spirobicyclic skeleton was constructed by RCM reaction. A new
silver(I)-promoted cyclization reaction of ∆6- and ∆7-α-iodoketones
was developed and applied for the pivotal carbon-carbon bond
formation. The scope and limitations of this methodology are also
presented.
changing the structures of the reactants.
epoxide
OPG
OPG
O
opening
O
O
O
1
O
OH
2
etherification
3
epoxidation
OPG
O
PGO
RCM
PGO
decarboxylative
allylation
Me
H
Me
H
Me
RO
=
R
2C CO2
The development of bacterial resistance to first-line antibiotic
drugs1 urged scientific community to search for new drug
candidates.2 These efforts involved, inter alia, the synthesis of
new antibiotic compounds, as well as structural modifications of
the existing ones.3 Consequently, new synthetic strategies are
constantly emerging, aiming at more efficient and flexible
syntheses necessary for SAR studies (of the analogues).4 In
2006, platensimycin was isolated from a Streptomyces platensis
strain, showing strong in vitro antibacterial activity toward broad-
spectrum Gram-positive bacteria, including methicillin-resistant
Staphylococcus Aureus (MRSA), vancomycin-intermediate S.
aureus (VISA), and vancomycin-resistant Enterococci (VRE).5
More importantly, it shows in vivo activity without toxicity,
especially when administered directly into cells.6 However, due
to a high rate of its clearance in the body, its pharmacokinetic
properties have to be improved,7 which calls for the development
R
allyl/methallyl
4
5
OMe
Diels-Alder
reaction
OH
R
PGO
Me
CO2
+
Me
H
CO2
R
CO2
TMSO
acid
S
6
7
( )-lactic
Knoevenagel
condensation
Scheme 1. Retrosynthetic analysis of the platensimycin core
Our retrosynthetic analysis of the platensimycin core is shown in
Scheme 1. It started with the C-O bond disconnection of the
tetrahydrofuran ring in 1 through the etherification transform.
The formation of the tricyclic skeleton 2 was considered to be
one of the key steps in the synthesis and this was planned to be
achieved through epoxide 3 opening by a ketone enolate. This
spirobicyclic system would be a product of the ring closing
metathesis reaction of diene 4, potentially obtainable by
stereoselective decarboxylative allylation of allyl/methallyl
diester 5. Cyclohexenone 5 could be synthesized by Diels Alder
reaction of Danishefsky’s diene 6 and chiral alkylidenemalonate
7 – a product of the Knoevenegel condensation of malonic ester
with the optically pure (S)-lactic acid derivative. We believed that
the absolute configuration of the chiral dienophile could dictate
the absolute configuration of the newly-created stereogenic
centre via the diastereoselective Diels Alder reaction, while all
other stereocenters could be established in the course of the
synthesis through the substrate control.
of
a flexible strategy for the synthesis of platensimycin
analogues.
OH
O
O
Me
HO
N
2C
H
OH
O
Me
(-)-Platensimycin
For this reason and due to the complex and intricate structure of
the platensimycin core, a number of enantioselective and
racemic (total and formal) syntheses have been reported so far.8
We set out to develop an alternative and flexible synthesis of the
platenismycin core relying on a chiral pool strategy, thus
potentially enabling the synthesis of its analogues by simply
The synthesis commenced with the preparation of the optically
pure diallyl alkylidene malonate 10a9 – a reactive partner for the
Yb-catalyzed Diels Alder reaction with Danishefsky’s diene 6
(Scheme 2).10 Indeed, the reaction of 10a with 6 provided
cyclohexenone 11a as a single isomer, but this transformation
turn out to proceed by a different mechanism. The product 11a
was actually formed by the Mukaiyama-Michael tandem
reaction:11 the corresponding acyclic intermediate could be
isolated when the reaction was performed at ambient
temperature. Notably, the reaction proceeded with a complete
diastereoselectivity, and the chiral information was successfully
transferred from the starting (S)-lactic acid to the product, which
was crucial for the enantioselective synthesis.
[a]
Dr. M. Trajkovic, Prof. Dr. Z. Ferjancic, Prof. Dr. R. N. Saicic,
Prof. Dr. F. Bihelovic
Faculty of Chemistry, University of Belgrade
Studentski trg 16, POB 51, 11158 Belgrade 118, Serbia
Tel: (+) 381 11 26 37 890
E-mail: filip@chem.bg.ac.rs; rsaicic@chem.bg.ac.rs
www.chem.bg.ac.rs
[b]
Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11000
Belgrade, Serbia
www.sanu.ac.rs
Supporting information for this article is available on the WWW
under http://www.angewandte.org.
This article is protected by copyright. All rights reserved.

10.1002/chem.201900497
Chemistry - A European Journal
COMMUNICATION
The addition of vinylmagnesium bromide afforded
a
O
TBSO
R
R
CO2
CO2
diastereomeric mixture of allylic alcohols, which were
subsequently acetylated (16). The deoxygenation of allylic
acetate 16 proceeded in almost quantitative yield,13 leading to
the formation of the metathesis precursor 17. The second
generation Grubbs catalyst effected this spirocyclization with
high efficiency.14 Finally, the TBS group in 18 was removed and
the free alcohol was oxidized to yield methylketone 19 in 56%
overall yield (over 8 steps, starting from diester 14).
TBSO
Me
R
CO2
OTBS
a)
b)
+
Me
H
R
CO2
Me
CHO
10a
10b
(85%)
8a/b
a:
9
RO
11a
11b
R
2C CO2
(96%)
OH
R=allyl
(87%)
(98%)
b: R=methallyl
OBn
OH
TBSO
TBSO
Me
TBSO
c)
e)
d)
Me
Me
H
H
(92%)
H
RO
2C
MethallylO2C
RO
R
2C CO2
R1
With gram quantities of the key bicyclic intermediate 19 in hand,
the stage was set for the crucial Cα-C3 bond formation. However,
we were unable to accomplish the intramolecular epoxide
opening by ketone enolate on the 3-like substrates, even in the
presence of Lewis acids.15
Me
12a
12b
1
(88%)
(96%)
=
14
13a
92%)
H,
1=Me, 98%)
(R
(R
13b
Scheme 2. Synthesis of the cyclohexene ring and diastereoselective
decarboxylative allylation. Reagents and conditions: a) TiCl4, Pyr, THF, 0 °C to
rt; b) Danishefsky’s diene 6, Yb(OTf)3, PhMe, rt to 120 °C; c) NaBH4, MeOH, 0
°C (dr = 19:1); d) [Pd(PPh3)4], CH2Cl2, rt; e) NaH, BnBr, TBAI, THF.
Another complementary strategy relied on radical cyclizations:
the functionalization of methyl ketone 19 in the α-position
afforded the corresponding xanthate (or iodide) which, under
either thermal or photochemical conditions, cyclized only
sluggishly, yielding an equimolar mixture of the two regioisomers
(Cα-C3 and Cα-C2). Encouraged with these initial results, we
wanted to test whether the yield as well as the regioselectivity of
the addition could be improved by switching the neutral radical
conditions for the ionic ones. To this end, we prepared ∆6-α-
iodoketone 20 (Scheme 4) as a model substrate, assuming that
silver(I) salts could promote the desired cyclization. Much to our
pleasure, the reaction indeed worked and, after optimization of
the reaction conditions, we found that the highest yield of the
The next task in the synthesis was Pd-catalyzed decarboxylative
allylation,12 which was initially tested on cyclohexenone 11a.
However, a complex mixture of products resulted under different
reaction conditions, and after extensive experimentation we
found that it was necessary to lower the substrate reactivity by
the carbonyl group reduction. Free allylic alcohol 12a turned out
to be an excellent substrate for this transformation and after
treatment with [Pd(PPh3)4] the wanted product 13a was isolated
in 92% yield, as a single diastereoisomer. The remarkable level
of stereoselectivity is most probably a consequence of a steric
environment on the neighboring carbon atom, bearing a bulky
substituent. Encouraged by the completely diastereoselective
formation of the new quaternary stereocenter, the whole
sequence was repeated with bismethallyl homologue 10b. This
proceeded uneventfully, and free allylic alcohol 13b was then
protected as benzyl ether: the entire sequence was performed
on a large scale, supplying us with 6 g of benzyl ether 14 in 77%
overall yield (after 5 steps, from dimethallylmalonate 8b).
cyclized
product
could
be
obtained
with
silver(I)
trifluoromethanesulfonate in CH2Cl2. This unprecedented
cyclization can be perfomed either in the absence or in the
presence of 2,6-lutidine, resulting in the formation of conjugated
cyclohexenone (21), or cyclohexanone (22 and 23), respectively.
O
O
O
I
O
a)
b)
+
(72%)
(74%)
According to our retrosynthetic analysis, the bicyclic
intermediate should be synthesized by a ring closing metathesis.
To this end, ester 14 was transformed to the corresponding
aldehyde 15 in two-steps (Scheme 3).
21
20
22
23
Scheme 4. Silver(I)-promoted cyclization of ∆6-α-iodoketone 20. Reagents
and conditions: a) AgOTf, CH2Cl2, rt, 30 min; b) AgOTf, 2,6-lutidine, CH2Cl2, rt,
15 min (22:23 = 1:1).
OBn
OBn
OBn
TBSO
TBSO
TBSO
d)
b)
c,
(78%)
Me
a,
(85%)
Me
Me
H
MethallylO2C
Me
H
Me
H
AcO
The scope of the reaction was tested on several substrates, and
the representative results are summarized in Table 1. The
reaction allowed for the smooth synthesis of cyclohexanone
(entries 1-5) and cycloheptanone (entry 6) derivatives in good to
excellent yields, without formation of any side product, thus
simplifying the purification/isolation steps.
It was surprising to witness the inertness of ∆5-α-iodoketones
toward cyclization,16 or even toward decomposition of the
starting material after prolonged reaction time (48 h). Moreover,
it proved necessary for all the substrates to possess a
trisubstituted double bond. The stability of ∆5-α-iodoketones
under the reaction conditions ruled out a formation of the
energy-rich α-acylcarbenium ions intermediates,17 as its
irreversible formation (AgI precipitation) would result in the
OHC
Me
15
14
16
OBn
OBn
OBn
TBSO
8
TBSO
e)
f)
h)
7
6
g,
9
Me
H
Me
H
O
5
10
1
(89%)
(98%)
(97%)
4
g)
(2.6
Me
α
2
3
17
18
19
Scheme 3. Synthesis of the spirobicyclic key intermediate 19. Reagents and
conditions: a) Dibal-H, Et2O, -50 °C; b) DMP, CH2Cl2; c) CH2=CHMgBr, Et2O;
d) Ac2O, Et3N, DMAP, CH2Cl2; e) Pd(OAc)2, Ph3P, Et3N, HCO2H, THF; f) 2nd
generation Grubbs catalyst, CH2Cl2; g) HF·Pyr, THF; h) DMP, CH2Cl2.
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10.1002/chem.201900497
Chemistry - A European Journal
COMMUNICATION
disappearance of the starting material. Therefore, we believe
that the reaction might proceed via a reversible silver(I)
complexation to the double bond, with a simultaneous formation
of the C-C bond and AgI.
We then applied the optimized cyclization conditions to α-
iodoketone 35, and much to our delight a smooth cyclization
occurred within minutes, affording the key tricyclic product 36 in
almost quantitative yield (Scheme 6).
OBn
OBn
Reaction
Conditions
Isolated
Yields
OBn
Entry
1
Substrate
Product
a)
b)
O
O
I
O
AgOTf
(1.5 eq)
(86%)
3 steps)
O
O
I
(over
36
2,6-lutidine
(1.2 eq), 15
min, rt
72%
74%
35
19
OBn
OBn
OBn
20
22, 23
c)
(85%)
e)
f)
d,
HO
H
H
(76%)
(41%)
O
I
O
H
AcO
HO
AgOTf
(1.5 eq), 30
min, rt
38
OH
2
37
OBn
39
O
21
20
h)
i)
g,
j)
AgOTf
(1.2 eq)
2,6-lutidine
(1.3 eq), 2
h, rt
I
O
O
(92%)
(90%)
(80%)
O
O
O
3
4
89%
90%
41
1
40
25, 26
24
Scheme 6. Synthesis of the tetracyclic platensimycin core 1. Reagents and
conditions: a) TMSOTf, DIPEA, CH2Cl2, 0 °C, then NIS, CH2Cl2, -78 °C; b)
AgOTf, 2,6-lutidine, CH2Cl2, rt; c) NaBH4, CeCl3, MeOH, -78 °C; d)
ClCH2SO2Cl, Pyr, DMAP, CH2Cl2; e) CsOAc, 18-crown-6, PhH; f) K2CO3,
MeOH, H2O; g) NBS, CH2Cl2, -40 °C; h) TBTH, AIBN, PhH, hν (Xenophot); i)
Li-naphthalenide, THF, -25 °C; j) DMP, CH2Cl2.
I
O
AgOTf
(1.2 eq), 30
min, rt
O
27
24
O
AgOTf
(1.5 eq)
2,6-lutidine
(1.7 eq),
I
It was necessary to perform the reaction in the presence of 2,6-
lutidine: in its absence the starting material/product decomposed
quickly due to the release of triflic acid. In the next step of the
synthesis, the reduction of the carbonyl group could not be
achieved with a satisfying level of diastereoselectivity, as the
unwanted diastereomer was obtained either as a major or as a
single product, under various reduction conditions. Therefore,
we relied on a two-step strategy comprising the inversion of
configuration of the opposite alcohol diastereomer 37, obtained
almost exclusively by the Luche reduction of 36. Unfortunately,
this inversion could not be performed by the standard Mitsunobu
protocol, probably due to considerable steric hindrance of the
OH-group in the starting alcohol. As an alternative, the alcohol
37 was first converted to the corresponding chloromesylate
which was treated with CsOAc/18-crown-6,18 to afford the
inverted acetate 38. After the hydrolysis of acetate 38, the fourth
(tetrahydrofuran) ring remains to be closed. Contrary to the
results of the other groups, this etherification could not be
catalyzed by acids due to the liability of the allylic fragment.
However, bromoetherification/radical debromination strategy
allowed for the formation of tetracycle 40 in 92% yield.
Debenzylation of 40 with lithium naphthalenide,19 followed by
DMP oxidation of allylic alcohol 41,20 afforded the target
platensimycin core 1, with all physical and spectral
characteristics identical to those previously reported in the
literature.5a
O
5
88%
29, 30
28
overnight, rt
AgOTf
(1.5 eq)
2,6-lutidine
(1.2 eq), 7
h, rt
O
O
I
6
67%
31
32, 33
Table 1: Representative examples of AgOTf promoted cyclization of ∆6- and
∆7-α-iodoketones
The reaction proceeds via the carbocationic intermediate, as
demonstrated by its trapping with methanol (Scheme 5). While
∆6- and ∆7-α-iodoketones can attain a geometrically favorable
transition state conformation, ∆5-α-iodoketones most probably
cannot. Intramolecular carbocation trapping by either the OH
group or by another suitably positioned double bond could lead
to more complex polycyclic products, and the results of this
study will be published in due course.
OMe
R
I
R
MeOH
O
Ag
O
I
O
(41%)
O
24
34
In summary, we exploited a chiral pool strategy for the
enantioselective synthesis of the platensimycin core. The
Mukaiyama-Michael domino reaction successfully transferred
the chiral information from the (S)-lactic acid derivative to the
cyclohexenone product. A palladium-catalyzed decarboxylative
Scheme 5. A plausable mechanistic pathway for Ag(I)-promoted cyclization of
∆6- and ∆7-α-iodoketones
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10.1002/chem.201900497
Chemistry - A European Journal
COMMUNICATION
allylation enabled the proper stereochemistry of the quaternary
stereocenter to be set. The crucial C-C bond was formed
efficiently, under mild reaction conditions by a newly-developed
method for the cyclization of ∆6- and ∆7-α-iodoketones with
silver(I) salts, which is complementary to radical methodology,
and may have general applicability.
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Acknowledgements
This work was supported by the Ministry of Education, Science
and Technological Development of the Republic of Serbia
(Project No. 172027) and by the Serbian Academy of Sciences
and Arts (Project No. F193). The authors acknowledge the
support of the FP7 RegPot project FCUB ERA GA No. 256716.
The EC does not share responsability for the content of the
article.
Keywords: antibiotics • natural products • total synthesis •
cyclization • silver
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Entry for the Table of Contents
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Milos Trajkovic,[a] Zorana Ferjancic,[a]
Radomir N. Saicic* [a,b] and Filip
Bihelovic* [a]
OH
OBn
OSiMe3
O
Me
Me
CO2
OMe
MgBr
AgOTf
O
O
O
2,6-lutidin
O
Page No. – Page No.
I
O
O
Enantioselective Synthesis of the
Platensimycin Core by Silver(I)-
Promoted Cyclization of ∆6-α-
Iodoketone
Me
Me
Enantioselective synthesis of the platensimycin core was achieved, relying on a
chiral pool strategy. The Mukaiyama-Michael domino sequence enabled
cyclohexenone ring to be closed diastereoselectively, while the quaternary
stereocenter was created by a highly stereoselective decarboxylative allylation. The
crucial C-C bond was formed by using a newly developed method for silver(I)-
promoted cyclizations of ∆6- and ∆7-α-iodoketones.
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