Total synthesis of (-)-microcarpalide from d-mannitol

Article abstract of DOI:10.1016/j.tetlet.2005.06.070

The total synthesis of the actin-targeting metabolite (-)-microcarpalide is described. Ring-closing metathesis of a dienic ester was used as the key step. d-Mannitol was used as the chiral pool material for the construction of the olefinic acid moiety as well as the olefinic alcohol moiety of the molecule.

Full text of DOI:10.1016/j.tetlet.2005.06.070

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5479–5481
Total synthesis of (ꢀ)-microcarpalide from D-mannitolq
Subhash Ghosh,* R. Vengal Rao and J. Shashidhar
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 April 2005; revised 9June 2005; accepted 14 June 2005
Available online 5 July 2005
Abstract—The total synthesis of the actin-targeting metabolite (ꢀ)-microcarpalide is described. Ring-closing metathesis of a dienic
ester was used as the key step. D-Mannitol was used as the chiral pool material for the construction of the olefinic acid moiety as well
as the olefinic alcohol moiety of the molecule.
Ó 2005 Elsevier Ltd. All rights reserved.
Microcarpalide 1 has been recently characterized as a
new secondary metabolite produced by an endophytic
fungus isolated from the bark of the tropical tree Ficus
microcarpa L.1 Bioassay-guided purification of the fer-
mentation broth using immunofluorescence microscopy
to test anticytoskeletol activity led to the isolation of a
new substance displaying remarkable disrupting action
on actin microfilaments, to which the structure 1 was
assigned. Microcarpalide was found to disrupt actin
microfilaments in approximately 50% of A-10 cells
(from rat smooth muscle).1 Moreover, it displayed weak
cytotoxicity towards mammalian cells,1 thus providing
an attractive tool for studying cell motility and metasta-
sis, and a potential lead structure to develop new anti-
cancer drugs. By virtue of such potent biological
activities, the apparently simple, yet stereochemically
demanding macrocyclic ring structure of this new fungal
metabolite has aroused the interest of synthetic organic
chemists world-wide, and as a result several total synthe-
ses have appeared.2 Herein, we report a convergent ap-
proach for the total synthesis of (ꢀ)-microcarpalide
starting from a cheap starting material, D-mannitol.
The retrosynthetic scheme for 1 was based on coupling
two partners, 3 and 4, via esterification (Scheme 1)
and subsequent ring closing metathesis (RCM).3
D-Mannitol was used as the chiral pool source for con-
struction of both the coupling partners.
Synthesis of the olefinic alcohol 3 (Scheme 2) com-
menced from 7, which was prepared as an inseparable
90:10 diastereomeric mixture in favour of the required
isomer according to the reported procedure.4 TBDPS
protection of the resulting alcohol afforded 8. Acetonide
OH
OH
OBn
OBn
OBn
OBn
n-C6H13
n-C6H13
O
O
OMEM
HOOC
O
1
O
OH
2
4
OTBDPS
OH
D-mannitol
n-C6H13
O
6
5
3
O
OMEM
Scheme 1. Retrosynthetic analysis.
Keywords: Microcarpalide; Ring-closing metathesis; Allylation; D-Mannitol.
q IICT Communication No. 050408.
*
Corresponding author. Fax: +91 40 27193108; e-mail: subhashbolorg3@yahoo.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.070

5480
S. Ghosh et al. / Tetrahedron Letters 46 (2005) 5479–5481
OH
OTBDPS
b
a
ref 4
O
O
D-mannitol
O
Me
O
Me
Me
6
Me
8
7
OTBDPS
OTBDPS
OTBDPS
c
d
f
AcO
HO
e
O
9
11
HO
HO
10
OTBDPS
OTBDPS
g
h
n-C6H13
n-C6H13
3
OMEM
13
OH
12
Scheme 2. Reagents and conditions: (a) TBDPSCl, imidazole, DMAP (cat), DMF, rt, 12 h, 95%; (b) 50% AcOH in water, rt, 12 h, 98%; (c) AcCl,
2,4,6-collidine, CH2Cl2, ꢀ78 °C, 85%; (d) MsCl, Et3N, CH2Cl2, 0°C; (e) K2CO3, MeOH, rt, 70% in two steps; (f) CH3(CH2)4MgBr, CuI, THF,
ꢀ23 °C, 70%; (g) MEMCl, DIPEA, CH2Cl2, 80%; (h) TBAF, THF, rt, 24 h 90%.
OBn
O
OBn
OH
a, b
c
O
OH
D-mannitol
O
O
6
O
OBn
O
15
OBn
14
OBn
OBn
f
d, e
O
g
CO2Et
CO2Et
h
O
O
OBn
O
OBn
16
17
OBn
OBn
i
CO2Et
CO2Et
HO
4
HO
OBn
18
OBn
19
Scheme 3. Reagents and conditions: (a) 2,2-dimethoxypropane, DMF, PTSA (cat); 80%; (b) NaH, BnBr, TBAI, THF, 0 °C to rt, 95%; (c) MeOH,
concd HCl, 0 °C to rt, 60%; (d) NaIO4, THF–H2O (2:1); (e) Ph3P@CHCO2Et, CH2Cl2, rt, 80% in two steps; (f) H2, Pd/C, EtOAc, n-BuNH2 (cat)
90%; (g) MeOH, HCl (cat), 0 °C to rt, 90%; (h) TPP, imidazole, I2, toluene, 80 °C, 70%; (i) LiOH, THF–H2O–MeOH (3:1:1), rt, 90%.
deprotection followed by selective acylation of the pri-
mary hydroxyl group gave 10, as a pure diastereomer
after the minor isomer had been easily separated by
standard silica gel column chromatography. Conversion
of 10 into the terminal epoxide 11 was achieved in two
steps in good yield. Epoxide opening with n-pentyl cup-
rate reagent afforded alcohol 12, which was then pro-
tected as its MEM-derivative 13. Finally, desilylation
of 13 afforded fragment 3.5
cleavage of the resulting diol followed by two-carbon
Wittig olefination gave 16 (E:Z = 7:3) (Scheme 3).
Olefin reduction with H2 over Pd–C followed by aceto-
nide deprotection with HCl (cat) in MeOH furnished
diol 18, which on treatment with TPP, imidazole and io-
dine in toluene afforded olefin ester 19.7 Saponification
of ester 19 in THF–methanol–water (3:1:1) provided
the desired acid fragment 4.
The synthesis of fragment 4 also commenced with D-
mannitol. Acetonide protection followed by benzylation
according to the reported procedure gave 14.6 Selective
monoacetonide deprotection afforded 15.6 Periodate
The union of the two fragments 3 and 4 was achieved by
using DCC to furnish the diene ester 2. Treatment of 2
with the Grubbs first generation catalyst under high
dilution (0.001 M in degassed CH2Cl2) furnished a
OBn
OH
OBn
OH
a
c
b
3
+
2
4
n-C6H13
n-C6H13
O
O
O
O
1
OMEM
OH
20
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, rt, 12 h, 80%; (b) 20 mol % of (PCy3)2Ru(Cl)2CH@Ph, CH2Cl2, reflux, 28 h, 70%; (c)
TiCl4, CH2Cl2, 0 °C, 0.5 h, 75%.

S. Ghosh et al. / Tetrahedron Letters 46 (2005) 5479–5481
5481
713–734; (e) Ishigami, K.; Kitahara, T. Heterocycles 2004,
63, 785–790; (f) Chavan, S. P.; Praveen, C. Tetrahedron
Lett. 2003, 44, 2873–2875; (g) Davoli, P.; Fava, R.;
Morandi, S.; Spaggiari, A.; Parti, F. Tetrahedron 2005,
61, 4427–4436; (h) Kumar, P.; Naidu, S. V. J. Org. Chem.
2005, 70, 4207–4210.
10:1 E:Z mixture of macrocyclic lactones, from which
the (E)-isomer 20 was isolated by silica gel column chro-
matography. Global deprotection of E-20 gave micro-
carpalide 1 (Scheme 4).2b The spectroscopic and
analytical data of compound 1 and other compounds
were in good agreement with literature data.2a,b,8
3. (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–
2238; (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
In conclusion, we have achieved a convergent total syn-
thesis of (ꢀ)-microcarpalide from the commercially
available, cheap starting material D-mannitol. The prep-
aration analogues and a study of their biological activi-
ties are currently under progress.
2001, 34, 18–19; (c) Furstner, A. Angew. Chem., Int. Ed.
¨
2000, 39, 3012–3043.
4. Mulzer, J.; Angermann, A.; Munch, W. Liebigs Ann. Chem.
¨
1986, 825–838.
5. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–
631.
6. Chakraborty, T. K.; Ghosh, S.; Rao, M. H. V. R.; Kunwar,
A. C.; Cho, H.; Ghosh, A. K. Tetrahedron Lett. 2000, 41,
10121–10125.
Acknowledgements
7. Garegg, P. G.; Samuclson, B. Synthesis 1979, 813–
814.
8. Selected physical data of E-20. Rf = 0.5 (silica, 20% EtOAc
We are thankful to CSIR (R.V.R.) and UGC (J.S.),
New Delhi for research fellowships. We are also thank-
ful to Dr. T. K. Chakraborty, Dr. A. C. Kunwar and the
Director, IICT for their support and encouragement.
27
1
in petroleum ether); ½aꢁD ꢀ35.5 (c 1.2, CHCl3); H NMR
data (CDCl3, 500 MHz): d 7.28–7.35 (m, 10H), 5.64–5.73
(m, 1H), 5.63 (dd, J = 15.7, 2.0 Hz, 1H), 5.15 (dt, J = 9.5,
4.6 Hz, 1H), 4.77–4.81 (m, 2H), 4.65 (d, J = 12.1 Hz, 1H),
4.54 (d, J = 11.9Hz, 1H), 4.47 (d, 1H, J = 12.8 Hz, 1H),
4.46 (d, J = 11.5 Hz, 1H), 4.07 (d, J = 4.1 Hz, 1H), 3.66–
3.78 (m, 4H), 3.53–3.56 (m, 2H), 3.38 (s, 3H), 2.61 (dd,
J = 14.3, 9.4 Hz, 1H), 2.22–2.32 (m, 2H), 2.11–2.20 (m, 1H),
1.96–2.04 (m, 1H), 1.54–1.59 (m, 3H), 1.26–1.32 (m, 8H),
0.88 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d
175.2, 138.7, 138.4, 131.6, 128.3, 128.2, 127.6, 127.5, 127.2,
126.4, 95.3, 78.1, 71.7, 71.5, 71.3, 67.4, 59.0, 36.0, 31.7, 31.1,
29.4, 25.0, 22.5, 14.0; HRMS (ESI) calcd for C34H48O7Na
[M+Na]+ 591.3297. Found 591.3307.
References and notes
1. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.;
Hemscheidt, T. Org. Lett. 2001, 3, 3479–3481.
2. (a) Murga, J.; Falmoir, E.; Garcia-Fortanet, J.; Carda, M.;
Marco, J. A. Org. Lett. 2002, 4, 3447–3449; (b) Gurjar, M.
K.; Nagaprasad, R.; Ramana, C. V. Tetrahedron Lett.
2003, 44, 2873–2875; (c) Davoli, P.; Spaggiri, A.; Casta-
gnetti, L.; Parti, F. Org. Biomol. Chem. 2004, 2, 38–47; (d)
Banwell, M. G.; Loong, D. T. J. Heterocycles 2004, 62,