Enantiospecific synthesis of (-)-muricatacin from l-(+)-tartaric acid

Article abstract of DOI:10.1016/j.tetasy.2006.09.017

Enantiospecific synthesis of (-)-muricatacin, a bio-active lactone comprising of a 5-hydroxyalkylbutan-4-olide structural component has been achieved from l-(+)-tartaric acid. The key step involves a disteroselective reduction of a C₂-symmetric

Full text of DOI:10.1016/j.tetasy.2006.09.017

Tetrahedron: Asymmetry 17 (2006) 2465–2467
Enantiospecific synthesis of (À)-muricatacin from L-(+)-tartaric acid
Kavirayani R. Prasad* and Pazhamalai Anbarasan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 19 July 2006; accepted 15 September 2006
Abstract—Enantiospecific synthesis of (À)-muricatacin, a bio-active lactone comprising of a 5-hydroxyalkylbutan-4-olide structural
component has been achieved from L-(+)-tartaric acid. The key step involves a disteroselective reduction of a C2-symmetric 1,4-diketone
derived from tartaric acid followed by a selective Grignard reagent addition.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
OH
Annonaceae acetogenins from the Annonaeceae plants
have attracted considerable interest owing to their poten-
tial biological properties including cytotoxic, antitumoral
and immunosuppressive activities.1 One of the common
structural components of these increasingly significant
natural products is the chiral 5-hydroxyalkylbutan-4-olide
nucleus. Some of the compounds possessing this structural
moiety have been shown to exhibit varied biological activ-
ities and also shown to be precursors for the synthesis of
complex natural products.2 One of the simple molecules
belonging to this group is muricatacin 1, isolated as a mix-
ture of enantiomers from the seeds of Anona muricata L.,
commonly known as sour soup or guanabana which is
grown commercially as a fruit crop in tropical regions.3
The enantiomers of muricatacin exhibited potent cytotoxic-
ity towards several human tumor cell lines. SAR studies
indicated that the activity is influenced by the nature of
the side chain,4 although, diastereomers of muricatacin
showed no significant affect on the cytotoxicity.5 Several
syntheses of muricatacin and its congeners have been devel-
oped in recent years due to the chemical and biological
properties of the molecule.6 However, a general methodol-
ogy for the synthesis of functionalized and non-functional-
ized muricatacin derivatives is still warranted. Herein, we
report such a methodology for the synthesis of muricata-
cin, which is amenable for access to diverse structural
derivatives.
O
muricatacin 1
O
2. Results and discussion
Our approach for the synthesis of muricatacin is based on
the strategy we developed for the enantioselective synthesis
of a-hydroxy aldehydes. We have recently shown that a
series of a-hydroxy aldehydes can be obtained in high
enantiomeric purity from L-(+)-tartaric acid involving
simple stereoselective transformations.7 As depicted in
retrosynthesis (Scheme 1), we anticipated the synthesis of
OBn
OH
OBn
H
11
11
11
OH
O
O
1
7
6
O
Me
OMe
R
R
N
O
O
O
O
O
OH
OH
O
O
O
O
O
R
R
R = C12H25
N
MeO
Me
4
3
2
*
Corresponding author. Tel.: +91 80 22932578; fax: +91 80 23600529;
e-mail: prasad@orgchem.iisc.ernet.in
Scheme 1. Retrosynthesis for (À)-muricatacin.
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.09.017

2466
K. R. Prasad, P. Anbarasan / Tetrahedron: Asymmetry 17 (2006) 2465–2467
Me
OMe
N
O
OH
O
O
O
O
O
C12H25MgBr, THF
0 oC, 1.5 h, 96%
O
O
C12H25
C12H25
C12H25
C12H25
K-Selectride, THF
78 oC, 2.5 h, 90%
−
O
N
O
3
OH
Me
OMe
4
2
OBn
i) FeCl3.6H2O, DCM
rt, 3 h, 87%
OBn
C12H25
O
O
MgBr
C12H25
C12H25
NaH, BnBr, DMF
0 oC to rt, 2.5 h, 92%
O
MgBr2:OEt2, DCM
78 oC, 4 h
ii) Pb(OAc)4, rt
Benzene, 1.5 h
H
−
OBn
6
5
OH
C12H25
OBn
i) O3/O2, Me2S, DCM:MeOH
0 oC, 4.5 h
OBn
C12H25
Pd/C, H2, MeOH
rt, 3 h, 83%
O
O
O
O
C12H25
ii) PCC, NaOAc, Celite, DCM,
rt, 1.5 h, 55% for 4 steps
OH
1
8
7
Scheme 2. Stereoselective synthesis of (À)-muricatacin.
muricatacin by elaboration of alcohol 7, which can be
obtained by a stereocontrolled Grignard addition to alde-
hyde 6. Aldehyde 6 can be accessed from diol 4, which in
turn can be achieved by the stereoselective reduction of
the diketone 3. Diketone 3 was derived by the addition of
dodecylmagnesium bromide to the bis-Weinreb amide 2
of tartaric acid.
synthesis of a number of functionalized and non-function-
alized derivatives of muricatacin. Further application of
this strategy for the synthesis of a number of bio-active
lactones is in progress.
Acknowledgements
Our synthetic sequence started with the addition of dodec-
ylmagnesium bromide to the bis-Weinreb amide 28 to
afford diketone 3 in excellent yield. Under conditions
optimized by us previously for the reduction of such di-
ketones,7 the reduction of 1,4-diketone 3 with K-Selectride
produced alcohol 4 as a single diastereomer. Protection
of the alcohol as the corresponding benzylether was
effected utilizing NaH/BnBr to yield dibenzylether 5 in
92% yield. Deprotection of the acetal in 5 furnished the
corresponding diol, which upon treatment with Pb(OAc)4
afforded aldehyde 6, which was used as such in the next
step.9 Reaction of aldehyde 6 with 3-butenylmagnesium
bromide in the presence of MgBr2ÆEt2O in dichlorometh-
ane provided alcohol 7.10 High selectivity associated with
the formation of alcohol 7 can be explained based on the
chelation controlled addition of the Grignard reagent to
the aldehyde. Ozonolysis of alcohol 7 yielded the corre-
sponding lactol, which on oxidation with PCC afforded
lactone 8 in 55% yield in four steps. Debenzylation of lac-
tone 8 with Pd/C proceeded cleanly to afford muricatacin
1. A synthetic sample of (À)-muricatacin 1 {mp 67–
67.5 °C, [a]D = À23.6 (c 1.1, CHCl3) lit.11 mp 67–68 °C,
[a]D = À23.3 (c 1.8, CHCl3)} exhibited spectral data identi-
cal to those reported in the literature (Scheme 2).
We thank the Department of Biotechnology (DBT), New
Delhi, for funding of this project. P.A. thanks the Council
of Scientific and Industrial Research (CSIR), New Delhi,
for a research fellowship.
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