A macrolactonisation approach to the cembrane carbocycle of bielschowskysin

Article abstract of DOI:10.1016/j.tetlet.2013.06.012

By judicious choice of a conformationally constraining unit to predispose cyclisation to a 15-membered ring, we present a straightforward strategy to a cembranolide precursor of bielschowskysin by the Sonogashira coupling of two readily prepared fragments (from d-glucose and l-malic acid) followed by a facile β-acylketene macrolactonisation reaction.

Full text of DOI:10.1016/j.tetlet.2013.06.012

Tetrahedron Letters 54 (2013) 4406–4408
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A macrolactonisation approach to the cembrane carbocycle
of bielschowskysin
Eugene G. Yang a, Karthik Sekar a, Martin J. Lear a,b,
⇑
a Department of Chemistry and Medicinal Chemistry Program, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
b Department of Chemistry, Graduate School of Science, Tohoku University, Aza Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
By judicious choice of a conformationally constraining unit to predispose cyclisation to a 15-membered
ring, we present a straightforward strategy to a cembranolide precursor of bielschowskysin by the Sono-
Received 2 May 2013
Revised 28 May 2013
Accepted 4 June 2013
Available online 11 June 2013
gashira coupling of two readily prepared fragments (from
D
-glucose and
L-malic acid) followed by a facile
b-acylketene macrolactonisation reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Bielschowskysin
Acylketene
Furanocembranoid
Macrocyclisation
Sonogashira
Bielschowskysin (1) was isolated and characterised in 2004 by
Marrero et al. from the Carribean octocoral Pseudopterogorgia kal-
los.1 Besides some moderate anti-malarial activity, this multicyclic
furanocembranolide shows strong and specific in vitro cytotoxicity
against two renal-cancer cell lines. Primarily driven by its complex
architecture and origin of biosynthesis, several groups have started
work towards achieving the total synthesis of 1, particularly to-
wards the key cyclobutane core.2 Herein, we report the synthesis
of an advanced macrolactone model system 3 in several attempts
to close to a bielschowskyane carbocyclic precursor (2) of 1
(Fig. 1; Scheme 1).
Continuing our retrosynthetic analysis, we planned to construct
the macrolactone 3 for carbocylisation studies to the bielschow-
skysin carbon framework 2 (Scheme 1). This required several dif-
ferentially protected alkynes 4 to be prepared from
L-malic
acid2b,5, as well as the ketoester 5 from diacetone- -glucose6 that
D
would serve as a conformationally constraining unit for macrocyc-
lisation studies. While this strategy offers the option of performing
lactonisation and C10/C11-alkylation before a Sonogashira macro-
cyclisation step, we present here our studies on performing Sono-
gashira coupling before a facile ketoester macrolactonisation step
via the b-acylketene 6.
One of our transannelation strategies to the bielschowskyane
framework is illustrated in Figure 1. We thus plan to perform con-
secutive allene/alkene-[2+2]2b and singlet-oxygen/diene-[4+2]3
photo-cycloadditions to construct the polycyclic core. Besides
being a clear antimalarial target, the endo-peroxide could be
opened with Co(II)TPP3 to give the ene-lactol spirocycle of 1.
This transannular approach to 1 thus led us to target the
cembranolide 2 (Scheme 1). It was envisioned that the C8-tertiary
alcohol could be installed at a late-stage under substrate control.
This conveniently allows a homopropargylic C8-alcohol (cf. 3) to
be oxidised directly to an allenone.4 Since there is precedent for
step-wise [2+2]-cycloaddition mechanisms,2a,c the stereochemis-
try of the allene may not be critical. Thus, a simple C8-oxidation
would serve as a mild method to generate the allenone 2 for trans-
annular [2+2]-cycloaddition studies.
First, we targeted to make the protected alkyne 4 (Scheme 2).
Starting from the known alcohol 7, prepared in two-steps from L-
malic acid,2b,5 7 was oxidised to the aldehyde and propargylated
under Luche conditions.7 The diasteroisomers 8 and 9 could be
separated by column chromatography and their identities were
O
O
1O2
C
hν
R
R
R
R
R
[2+2]
[4+2]
OH
R
O
CoII(TPP)
O
O
O
O
R
homolytic
rearrangement
R
⇑
Corresponding author. Tel.: +81 22 795 3554; fax: +81 22 795 6566.
E-mail address: Martin.Lear@m.tohoku.ac.jp (M.J. Lear).
Figure 1. Proposed transannular [2+2]/[4+2] reaction sequence via singlet-oxygen
diene addition and peroxide homolysis.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.012

E. G. Yang et al. / Tetrahedron Letters 54 (2013) 4406–4408
4407
OH
Br
Br
HO
(cf. Fig. 1)
4
OH
O
O
O
C
O
H
O
O
HO8
O
1
O
8
O
OH
O
1
a - f
g, h
H
O
OH
O
13
H
OAc
O
10
H
H
HO
O
[4+2] and [2+2]
cycloadditions
O
O
O
BzO
OAc
O
BzO
O
diacetone-D-glucose
I
11
12
1
2
Bielschowskysin ( )
I
I
10
X
13
OTBDPS
5
O
O
O
Sonogashira
HO
i
j, k
l
C
O
O
O
O
O
O
6
10
X
O
O
HO
TBDPSO
O
4
O
BzO
O
8
CO2Et
13
14
5
11
X
O
4
H
O
I
10
12
O
Scheme 3. (a) IBX, EtOAc, reflux, 18 h; (b) Ph3P = CO2Me, DCM, rt, 18 h, 83% (two-
steps); (c) H2, Pd/C, MeOH, rt, 16 h; (d) LiAlH4, THF, 0 °C to rt, 3 h; (e) BzCl, NEt3,
DMAP, DCM, rt, 12 h; (f) I2, MeCN/H2O (20:1), rt, 20 h, 84% (four-steps); (g) NaIO4,
MeOH/H2O (2:1), rt, 1 h; (h) PPh3, CBr4, NEt3, DCM, 0 °C, 1 h, 88% (two-steps); (i)
Me2CuLi, ether, À78 °C, 1 h; I2, À78 °C, 30 min; 0 °C, 30 min, 59%; (j) K2CO3, MeOH,
rt, 2.5 h, 95%; (k) IBX, EtOAc, reflux, 3 h; (l) ethyl diazoacetate, SnCl2, DCM, rt, 3 h,
72% (two-steps).
1
O
O
13
O
O
H
3
O
O
EtO2C
Macrolactonisation via ketene
then C11/C12-carbocyclisation
5
Scheme 1. Retrosynthetic analysis of 1.
Having the appropriate fragments in hand, we coupled the al-
kyne 4 and vinyl iodide 5 under Sonogashira conditions to give
15 (Scheme 4). Subsequent refluxing of 15 in toluene for 8 h af-
fected a smooth cyclisation to the macrolide 16 in 60% yield over
two-steps. This utilised the specific property of b-ketoesters to
form an acylketene 6 under thermal conditions.16 While earlier
macrolactonisation studies of ketoesters used the protected form
of the enol as the dioxolenone,17 it has recently been shown18 that
the b-ketoester is sufficient. Formic acid cleavage of the primary
TBS ether gave the alcohol 17.
O
OH
a, b
O
OH
O
OH
O
O
O
+
7
8
9
c, d
OTBDPS
OH
e, f, g
OH
O
O
C
10
4
OTBS
[X= OTBS]
Conversion of the hydroxyl group of 17 to a halide proved to be
more difficult than anticipated, possibly due to interference from
the ketoester and enyne. Finally, it was found that refluxing 17 in
CCl4 with PPh3 and MgO gave a 55% yield of the chloride 3 (addi-
tional details and reaction conditions explored are provided in
Supplementary data). A few things to point out here are that differ-
ent unidentified side products were observed, with and without
magnesium oxide, and the use of trichloroacetonitrile was not suc-
cessful at all, even though it has been reported19 to be a better
chlorinating agent than CCl4.
Scheme 2. (a) IBX, EtOAc, reflux, 3 h; (b) propargyl bromide, zinc, THF/sat. NH4Cl
(aq.) (1:5); 35% for 8; 38% for 9/10 (5:1); (c) ClCH2CO2H, PPh3, DIAD, PhCH3, rt, 14 h;
(d) K2CO3, MeOH, rt, 2 h, 47% (two-steps); (e) TBDPSCl, Im, DMF, rt, 12 h; (f) TFA,
THF/H2O (4:1), rt, 68 h, 83% (two-steps); (g) TBSCl, Im, DMF, rt, 16 h, 94%.
confirmed by comparison of their NMR data with the literature8
and by NOE experiments of its benzylidene derivative. The 1,3-
syn isomer 9 was isolated mixed with the allenyl alcohol 10
(formed due to the c-addition of the propargyl zinc species). Mits-
unobu inversion of 9–8 with chloroacetic acid9 went smoothly
which, after cleavage of the chloroacetate, was found identical to
the 1,3-anti isomer 8 that was directly isolated from the propargy-
lation step. Interestingly, the reverse reaction (anti-8 to syn-9) did
not proceed and led to decomposition of 8. Finally, protecting
group manipulation with the TBDPS and TBS ethers gave 4
[X = OTBS] in good yield over three steps.
With the halide in hand, we attempted the intrameolcular
alkylation with caesium carbonate in THF similar to Deslong-
champ’s macroalkylation procedure.20 However, instead of obtain-
ing the desired carbocycle
3 [X = Cl], the alcohol 17 was
regenerated, presumably via hydrolysis of an O-alkylated interme-
diate (18). A case had been reported with a similar b-diester21 and
the problem was circumvented by performing the alkylation first;
however, various attempts to perform the alkylation of the ketoes-
ter, either in an inter- or intra-molecular sense, did not proceed in
our case (see Supplementary data).
In seeking a solution to our problem, we conducted a model
study using 20 and 21 (see Supporting Information). In contrast
to the macrolactone 3 [X = Cl], the preparation of the halides
20/21 from their corresponding alcohols proceeded cleanly in
high yields. Despite these model cases, we were unsuccessful un-
der numerous conditions to solve the intramolecular C-alkylation
step.
In summary, we have explored the use of two readily prepared
fragments, an alkyne-diol 4 and a ketoester-vinyl iodide 5, to
onstruct the macrolactone skeletal structure 3 of bielschowskysin
1. We were, however, unable to form the carbocyclic C11/C12-
bond connection (cf. 2 or 19) through various alkylation and
aldol-studies.22 An important step forward in the present study is
Next, we targeted to make the ketoester 5 (Scheme 3). Here, we
began with diol 11, which was readily prepared in 70% yield over
six-steps from commercially available diacetone-D-glucose, with
minor modifications to the literature procedures.6,10 The Z-vinyl io-
dide was prepared using the Tanino–Miyashita olefination meth-
od,11 which gave a higher yield than the Stork–Zhao olefination
method.12 The diol 11 was oxidatively cleaved to the aldehyde
and converted into the dibromoolefin 12 via Jiang and Ma’s modi-
fication13 of the Ramirez dibromoolefination method14 in 88% yield
over two steps. Treatment of 12 with Me2CuLi and quenching with
iodine gave the Z-vinyl iodide 13 stereoselectively. The stereo-
chemistry of the vinyl iodide and furanose moiety was confirmed
via single crystal X-ray crystallography (Fig. 2). The benzoate pro-
tecting group was cleaved to give 14. The primary alcohol was then
oxidised to the aldehyde and homologation, as per the Holmquist
and Roskamp’s method,15 gave the b-ketoester 5 in a direct and
clean fashion.

4408
E. G. Yang et al. / Tetrahedron Letters 54 (2013) 4406–4408
Figure 2. ORTEP representation for single-crystal X-ray of 13.
Supplementary data
Supplementary data (experimental procedures and character-
TBDPSO
O
a
b
isation data for all new compounds, as well as alkylation model
studies, associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.06.012. Coordinates
for 13 (CCDC 924516) have been uploaded to the Cambridge Crys-
tallographic Data Centre (http://www.ccdc.cam.ac.uk/)).
10
4
X
O
c
OH
5
H
O
10
C
O
O
OH
EtO
TBSO
O
O
15
6 [X= OTBS]
References and notes
TBDPSO
TBDPSO
HO
O
O
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H
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O
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11
3 [X= Cl]
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Acknowledgments
22. Ring-closing metathesis (RCM) studies to form the carbocyclic C11/C12-bond
We thank the Ministry of Education of Singapore for funding
(AcRF Tier-2 Grant T206B1112), PhD graduate scholarships (to
E.G.Y. and K.S.) and Tan Geok Kheng for assistance in solving the
X-ray crystal structure of the Z-vinyl iodide 13.
connection of
1 will be published in due course. For RCM work on
cembranolides, see Ref. 2c and Donohoe, T. J.; Ironmonger, A.; Kershaw, N.
M. Angew. Chem., Int. Ed. 2008, 47, 7314; Takamura, H.; Iwamoto, K.; Nakao, E.;
Kadota, I. Org. Lett. 2013, 15, 1108–1111.