Total synthesis of (-)-muricatacin

Article abstract of DOI:10.1016/j.tetlet.2011.08.160

A total synthesis of (-)-muricatacin has been achieved using a commercially available starting material and our furan approach to oxacyclic systems, the proven scope of which is thus broadened.

Full text of DOI:10.1016/j.tetlet.2011.08.160

Tetrahedron Letters 52 (2011) 5983–5986
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of (ꢀ)-muricatacin
Maria González a, Zoila Gándara a, Berta Covelo b, Generosa Gómez a, , Yagamare Fall a,
⇑
⇑
a Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
b Servicio Determinación Estructural y Proteómica, CACTI, Universidad de Vigo, 36310 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of (ꢀ)-muricatacin has been achieved using a commercially available starting material
and our furan approach to oxacyclic systems, the proven scope of which is thus broadened.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 22 June 2011
Revised 2 August 2011
Accepted 26 August 2011
Available online 5 September 2011
Keywords:
Butenolide
Singlet oxygen
Natural products
Total synthesis
c
-Lactone
Butenolides, and the corresponding saturated
c
-lactones, are
activity has stimulated significant interest in the synthesis of muri-
catacin.4 Here, we report a new synthesis that may be efficient and
flexible enough to give access to potentially interesting new
analogues.
found as structural subunits in a wide range of biologically active
natural products,1 some of which are depicted in Figure 1. They
are often used as intermediates for the synthesis of biologically sig-
nificant natural products.2
As outlined in Scheme 1, we anticipated that once the relatively
(ꢀ)-Muricatacin (1) was discovered when isolated from the
seeds of the tropical evergreen Annona muricata L. (Annonaceae),3
commonly known as ‘sour sop’ or ‘guanabana’. Both the enantio-
mers are found in nature, and both exhibit the same potent cyto-
toxicity towards several human tumour cell lines.3 This biological
inexpensive and readily available chiral reagent D-malic acid (4)
had been transformed into chiral furan 5, the stage would be set
for the synthesis of 1 by what we call our furan approach to oxacyclic
systems.5 Accordingly, aldehyde 18, containing the desired muricat-
acin side chain, hence the precursor of compound 5 was prepared as
O
O
OH
(-)-muricatacin
1
O
O
HO
OH
OH
HO
O
iso-cladospolide B
2
OH
O
OH
vitamin C 3
Figure 1. Some natural products containing butenolide or c-lactone moieties.
⇑
Corresponding authors. Fax: +34 986 81 22 62.
E-mail addresses: ggomez@uvigo.es (G. Gómez), yagamare@uvigo.es (Y. Fall).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.160

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M. González et al. / Tetrahedron Letters 52 (2011) 5983–5986
O
5
OTBDPS
C12H25
OH
O
O
1
OH
O
HO
O
OH
4
Scheme 1. Retrosynthetic analysis of (ꢀ)-muricatacin 1.
O
OH
O
O
O
iii
i
ii
O
v
HO
O
OTBS
OTBDPS
OH
OH
O
O
4
7
O
6
HO
vi
OTBDPS
OTBS
OTBS
OH
iv
10
MeO
MeO
+
OTBS
OTBDPS
O
9
8
O
H
OTBS
11
O
OTBDPS
OTBS
OTBDPS
OH
viii
ix
vii
PivO
PivO
12
13
OTBDPS
OTBDPS
CHO
x
xi
PivO
HO
PivO
PivO
15
14
OTBDPS
OTBDPS
OTBDPS
xiii
xii
O
C9H19
C9H19
C9H19
18
17
H
16
Scheme 2. Reagents and conditions: (i) cyclohexanone, BF3ꢁOEt2, Et2O, 0 °C to rt (93%); (ii) (a) BH3ꢁSMe2, B(OMe)3, THF, 0 °C to rt; (b) TBSCl, Imid, DMAP, DMF, rt (57% from 4,
three steps); (iii) NaOMe, MeOH, rt (97%); (iv) TBDPSCl, Imid, DMAP, DMF, rt (71%); (v) DIBAL, CH2Cl2, ꢀ78 °C (10, 77%; 11, 12%); (vi) NaBH4, MeOH, 0 °C (87%); (vii) PivCl,
DMAP, pyr (90%); (viii) HF/pyr, THF, pyr, 0 °C to rt (80%); (ix) TEMPO, BAIB, CH2Cl2 (97%); (x) C10H21IPPh3, n-BuLi, THF, (86%); (xi) H2, Pd/C, MeOH, rt (96%); (xii) DIBAL-H,
CH2Cl2, ꢀ78 °C (97%); (xiii) TEMPO, BAIB, CH2Cl2 (97%).
OTBDPS
OTBDPS
i
EtO
EtO
O
C9H19
C9H19
18
H
OEt
OEt
OH
20
19
OTBDPS
ii
C9H19
EtO
OH
21
OEt
iii
O
5
OTBDPS
Scheme 3. Reagents and conditions: (i) 19, n-BuLi, THF, ꢀ78 to 0 °C (89%); (ii) H2, Lindlar catalyst, hexane, rt; (iii) HCl, or PPTS (72%).

M. González et al. / Tetrahedron Letters 52 (2011) 5983–5986
5985
O
i
O
O
20
OTBDPS
5
OTBDPS
ii
iii
O
O
21
OTBDPS
O
O
OH
(-)-muricatacin
1
Scheme 4. Reagents and conditions: (i) (a) O2, MeOH, rose Bengal, Hünig’s base, h
(99%); (iii) TBAF, THF, rt (80%).
m; (b) NaBH4, CeCl3ꢁ7H2O, MeOH; (c) HCl, MeOH (71%, three steps); (ii) H2, Pd/C, MeOH, rt
Figure 2. X-ray structure of 1.
shown in Scheme 2. Reaction of
D
-malic acid (4) with cyclohexanone
in the next reaction without further purification. Treatment of
allylic alcohol 21 with catalytic pyridinium toluene-p-sulphonate
(PPTS) or HCl resulted in cyclisation with the loss of two molecules
of ethanol, affording the desired furan.8
With furan 5 in hand, the stage was set for the crucial oxidation
step using singlet oxygen (Scheme 4). Furan 5 was subjected to sin-
glet oxygen oxidation followed by sodium borohydride reduction
under Luche’s conditions to give an intermediate hydroxy acid
which underwent acid catalysed in situ lactonization, affording
butenolide 20 in 71% overall yield (three steps). Catalytic hydroge-
nation of 20 gave 21 in 99% yield. Treatment of 21 with TBAF affor-
ded target compound 1.9
in the presence of a Lewis acid6 gave acid 6 in 93% yield. Reduction of
the latter with borane dimethyl sulphide complex7 afforded a rather
labile alcohol that without further purification was protected as tert-
butyldimethylsilyl ether 7 (57% yield from 4), and removal of the
cyclohexylidene protecting group with NaOMe afforded hydroxyes-
ter 8 in 97% yield. Protection of the hydroxyl group of 8 afforded tert-
butyldiphenylsilylether 9 in 71% yield, and the reaction of 9 with DI-
BAL-H gave the desired alcohol 10 (77%) together with an aldehyde
(11, 12%) that was easily transformed into 10 by the reduction with
sodium borohydride in methanol (87% yield). Alcohol 10 was pro-
tected as its pivaloyl ester 12 (90% yield), and the selective removal
of the TBS protecting group of 12 afforded alcohol 13 (80%), which
upon TEMPO oxidation gave aldehyde 14 in 97% yield. Wittig reac-
tion of aldehyde 14 afforded 86% yield of alkene 15, which upon cat-
alytic hydrogenation gave 16 in 96% yield. Deprotection of the
primary hydroxyl group of 16 afforded 97% yield of alcohol 17, and
TEMPO oxidation of 17 gave 94% yield of aldehyde 18.
The structure of 1 was unambiguously confirmed as that shown
in Figure 2 by X-ray crystallographic analysis of crystals obtained
by recrystallization from hexane.10
The high diastereoselectivity observed in the conversion of 5 to
20 can be explained by assuming that the reduction of intermedi-
ate 23 takes place via a Felkin–Anh model11 (Scheme 5).
In conclusion, we have carried out an enantioselective synthesis
of (ꢀ)-muricatacin from commercially available starting material
using a method developed by our research group for oxacyclic sys-
tems. Work is now in progress on the synthesis of new analogues
of muricatacin with a view to their biological evaluation.
Aldehyde 18 was easily transformed into furan 5 in two steps
(64% yield) as shown in Scheme 3. Treatment of 18 with the lith-
ium derivative of alkyne 19 gave a mixture of epimeric propynyl
alcohols 20 which was hydrogenated over Lindlar catalyst, provid-
ing a mixture of diastereoisomeric (Z)-alkenes 21 which was used

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M. González et al. / Tetrahedron Letters 52 (2011) 5983–5986
O
O
O
20
OTBDPS
5
OTBDPS
O2, MeOH, rose Bengal
Hünig's base, hν
1) NaBH4, CeCl3.7H2O, MeOH
2) HCl, MeOH
O
HO
O
O
O
HO
23
OTBDPS
OTBDPS
22
TBDPSO
O
O
C12H25
HO
HO
24
OTBDPS
H
-
H
HCl
CO2H
Felkin-Ahn model
20
Scheme 5. Mechanistic explanation of the diastereoselectivity observed in the conversion of 5 to 20.
6686–6689; (h) Popsavin, V.; Krstic´, I.; Popsavin, M.; Srec´o, B.; Benedekovic´, G.;
Acknowledgements
´
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This work was supported by a Grant from the Xunta de Galicia
(PGIDIT04BTF301031PR). We also thank the NMR service of the
CACTI, University of Vigo, for NMR studies and X-ray structure
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Supplementary data
Supplementary data associated (experimental procedures and
spectral data) with this Letter can be found, in the online version,
at doi:10.1016/j.tetlet.2011.08.160.
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