Stereoselective synthesis of (-)-microcarpalide

Article abstract of DOI:10.1016/j.tetlet.2006.11.027

A stereoselective approach for the synthesis of the bio-active decanolactone (-)-microcarpalide was achieved from chiral pool tartaric acid. The synthesis of pivotal intermediates en route to the decanolactone was achieved from α-benzyloxy aldehydes deriv

Full text of DOI:10.1016/j.tetlet.2006.11.027

Tetrahedron Letters 48 (2007) 309–311
Stereoselective synthesis of (À)-microcarpalide
Kavirayani R. Prasad,* Kamala Penchalaiah, Amit Choudhary and Pazhamalai Anbarasan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 6 September 2006; revised 21 October 2006; accepted 2 November 2006
Available online 27 November 2006
Abstract—A stereoselective approach for the synthesis of the bio-active decanolactone (À)-microcarpalide was achieved from chiral
pool tartaric acid. The synthesis of pivotal intermediates en route to the decanolactone was achieved from a-benzyloxy aldehydes
derived from L- and D-tartaric acid.
Ó 2006 Elsevier Ltd. All rights reserved.
(À)-Microcarpalide (1), is a 10-membered lactone of
polyketide origin isolated by Hemscheidt’s group from
the fermentation broths of an unidentified endophytic
fungi.1 Microcarpalide is similar in structure to other
fungal decanolides such as herbarumin I (2), herbarumin
II (3) and lethaloxin (4) and is found to be weakly cyto-
toxic to mammalian cells and acts as a microfilament
disrupting agent (Fig. 1). Since the isolation of micro-
carpalide, a number of syntheses have appeared in the
past few years.2 Most of the approaches towards the
synthesis of microcarpalide were centred either on ring
closing metathesis (RCM) of a suitably protected diene
ester of type 6 or on Yamaguchi lactonization of a suit-
able linear hydroxy acid as the key step.
OH
HO
HO
OH
O
O
O
O
OH
Microcarpalide 1
Herbarumin I 2
HO
HO
HO
O
O
HO
O
OH
O
O
O
Lethaloxin 4
Herbarumin II 3
Figure 1. Bioactive fungal decanolactones.
OBn
OBn
OH
OH
OBn
OBn
C6H13
C6H13
C6H13
O
O
O
O
O
O
OBn
OBn
O
OH
5
1
6
OH
OBn
OBn
OH
H
HO
C6H13
C6H13
OH
-tartaric acid
O
O
OH
D
9
7
6
+
O
OH
OBn
O
O
OPG
OH
HO
OH
H
OH
O
OBn
OBn
10
L
-tartaric acid
8
Scheme 1. Retrosynthesis of (À)-microcarpalide 1.
Keywords: Decanolide; Microcarpalide; Stereoselective reduction; Tartaric acid.
*
Corresponding author. Tel.: +91 80 22932578; fax: +91 80 23600529; e-mail: prasad@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.027

310
K. R. Prasad et al. / Tetrahedron Letters 48 (2007) 309–311
Continuing efforts from our laboratory on enantioselec-
tive synthesis of natural products from chiral pool tar-
taric acid has resulted in the synthesis of a number of
bio-active pheromones and styryl lactones.3 A pivotal
step in our approach is the enantioselective synthesis
of a-benzyloxy aldehydes, which serve as excellent syn-
thons for further elaboration. We envisaged the synthe-
sis of (À)-microcarpalide 1 through the key precursor 5,
which in turn can be derived from the RCM reaction of
diene ester 6. Assembly of the alcohol and acid compo-
nents 7 and 8 of the diene ester was envisaged from alde-
hydes 9 and 10, which can be derived from D- and L-
tartaric acid, respectively (Scheme 1).
The synthetic sequence for alcohol component 7 com-
menced with the addition of n-hexylmagnesium bromide
to bis-Weinreb amide 114 derived from D-(À)-tartaric
acid affording diketone 12 in a 95% yield. Under condi-
tions optimized by us for the reduction of these types of
diketones,5 the reduction of 12 with L-Selectride fur-
nished a single diastereomer of 1,4-diol 13 in a 92%
yield. Subsequent protection of diol 13 under standard
conditions afforded dibenzyl ether 14. Facile deprotec-
tion of the acetonide6 in 14 was accomplished with Fe-
Cl3Æ6H2O to yield diol 15 in a 87% yield. Treatment of
diol 15 with Pb(OAc)4 furnished aldehyde 9, which on
subsequent allylation under Keck allylation conditions7
O
O
OMe
N
O
O
C6H13MgBr, THF
0 oC, 2 h, 95%
L-Selectride, THF
C6H13
Me
−78 oC, 2 h, 92%
N
Me
C6H13
OMe O
O
O
O
11
12
O
BnO
C6H13
O
HO
FeCl3.6H2O, DCM, rt
2.5 h, 87% for 2 steps
NaH/DMF, BnBr
rt, 2 h
C6H13
C6H13
OH
C6H13
O
OBn
O
14
13
OBn OH
SnBu3
OBn
OBn
MgBr2.Et2O
Pb(OAc)4
C6H13
OH OBn
15
H
−78 oC, DCM, 3 h
C6H13
C6H13
benzene, rt, 1.5 h
C6H13
OH
7
74% for 2 steps
O
9
Scheme 2. Synthesis of homoallylic alcohol 7.
O
O
OMe
N
O
O
L-Selectride, THF
3 h, −78 °C, 98%
MgBr
Me
N
Me
2
THF, 0 °C, 2 h, 87%
2
O
OMe O
O
O
16
17
i) O3, DCM:MeOH (4:1)
Me2S, NaHCO3, 5 h
ii) NaBH4, MeOH, 1.5 h
84%
HO
O
BnO
2
O
NaH, DMF, BnBr
rt, 2 h, 97%
2
2
2
O
O
OH
OBn
19
18
i) Imidazole, DMAP (cat)
DMF, TBDPSCl, 3 h, rt, 84%
OR OBn OH
2
BnO
2
O
OH
2
.
ii) FeCl3 6H2O, DCM
HO
2
OH OBn OR
O
2 h, 10 °C, 66%
OBn
21
R =TBDPS
20
OH
O
CH2=CHMgBr/MgBr2.OEt2
DCM, −78 °C, 2 h
Pb(OAc)4, C6H6
rt, 1.5 h
OR
H
2
OBn
OBn OR
77% for two steps
22
10
OBn
O
i) IBX, DMSO, rt, 2 h
i) NaH, DMF
OBn
OH
ii) NaClO2, NaH2PO4
DMSO, H2O, rt, 2 h
96% for two steps
BnBr, 2 h, rt, 94%
ii) TBAF, THF
rt, 2 h, 94%
OH
OBn
OBn
8
23
Scheme 3. Synthesis of 6-heptenoic acid fragment 8.

K. R. Prasad et al. / Tetrahedron Letters 48 (2007) 309–311
311
OBn
pound. Since the conversion of 5 to (À)-microcarpalide
has already been reported in the literature, the present
sequence constitutes a formal total synthesis (Scheme 4).
OBn
DCC, DMAP
rt, 25 h, 43%
Grubbs' catalyst
DCM, rt
C6H13
7
8
+
O
O
OBn
6
OH
OH
OBn
Acknowledgements
OBn
We thank the Department of Science and Technology,
New Delhi, for funding of the project. P.A. thanks
CSIR, New Delhi, for a research fellowship.
C6H13
C6H13
ref. 2e
O
O
O
O
OH
OBn
(−)-microcarpalide 1
5
Scheme 4. Synthesis of (À)-microcarpalide 1.
References and notes
1. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.;
Hemscheidt, T. Org. Lett. 2001, 3, 3479.
with allyltributyltin furnished the required threo alcohol
7 as the sole diastereomer ([a]D +17.1 (c 1.7, CHCl3),
lit.2e [a]D +17.4 (c 1.5, CHCl3)) (Scheme 2).
2. (a) Marco, J. A.; Fortanet, J. G.; Murga, J.; Falomir, E.;
Carda, M. J. Org. Chem. 2005, 70, 9822; (b) Marco, J. A.;
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R.; Chandrakumar, A.; Anbarasan, P. Tetrahedron: Asym-
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Synthesis of the olefinic acid fragment 8 was initiated by
the addition of 3-butenylmagnesium bromide to bis-
Weinreb amide 164 derived from L-(+)-tartaric acid to
yield diketone 17 in an 87% yield. L-Selectride reduction
of diketone 17 afforded diol 18 as a single diastereomer
in a 98% yield. Alcohol 18 was converted to dibenzyl-
ether 19, which on ozonolysis followed by reduction
with NaBH4 afforded diol 20 in an 84% yield. The pri-
mary alcohol groups in 20 were protected as the corre-
sponding tert-butyldiphenylsilyl (TBDPS) ethers. Next,
a facile deprotection of the acetonide with FeCl3Æ6H2O6
furnished diol 21. Treatment of diol 21 with Pb(OAc)4
resulted in aldehyde 10, which on reaction with vinyl
magnesium bromide in the presence of MgBr2ÆOEt2 in
dichloromethane produced threo alcohol 22 as a single
diastereomer.8 Protection of the secondary alcohol
group in 22 as benzyl ether and deprotection of the silyl
ether afforded 23 in a high yield. Oxidation of the pri-
mary alcohol with IBX gave the aldehyde, which on fur-
ther oxidation with NaClO2 yielded acid 8 in a 96%
yield. The spectral data and the physical properties
([a]D +16.6 (c 0.9, CHCl3), lit.2h [a]D +16.8 (c 0.7,
CHCl3)) of acid 8 were in complete agreement with
those reported in the literature (Scheme 3).
4. (a) Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F., Jr.; Meyer, D. T.; Jadhav, P. K.; De
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metry 2005, 16, 1897; (b) Prasad, K. R.; Chandrakumar, A.
Synthesis 2006, 2159.
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Magrath, J. J. Org. Chem. 1997, 62, 6684.
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8. Use of ethereal solvents decreased the diastereomeric ratio.
A similar outcome in the addition of vinylmagnesium
bromide to non-functionalized benzyloxy aldehydes in non-
ethereal solvent has been reported. Carda, M.; Rodriguez,
S.; Gonzalez, F.; Castillo, E.; Villanueva, A.; Marco, J. A.
Eur. J. Org. Chem. 2002, 15, 2649.
After successfully obtaining the alcohol and acid frag-
ments, the synthesis of (À)-microcarpalide via ester 6,
employing the procedure reported by Davoli et al.2e
was undertaken. Accordingy, DCC/DMAP mediated
coupling of alcohol 7 with acid 8 generated ester 6
[a]D +2.0 (c 2.0, CHCl3, lit.2e [a]D +1.9 (c 1.4, CHCl3),
which on ring closing metathesis (RCM) with Grubbs
1st generation catalyst in dichloromethane produced 5.
Interestingly, RCM reaction using Grubbs 2nd genera-
tion catalyst produced an E/Z mixture of decanolide 5
in a 33% yield with 64% of unreacted starting com-