Stereoselective total synthesis of (+)-aspicilin

Article abstract of DOI:10.1016/j.tetlet.2006.05.043

A stereoselective synthesis of (+)-aspicilin is described. Regio- and stereoselective functionalization by intramolecular participation of the sulfinyl group, ene reaction, and macrolactonization by Wadsworth-Emmons reaction employing Masamune-Roush proto

Full text of DOI:10.1016/j.tetlet.2006.05.043

Tetrahedron Letters 47 (2006) 5595–5597
Stereoselective total synthesis of (+)-aspicilinI
Sadagopan Raghavan* and T. Sreekanth
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 8 May 2006; accepted 9 May 2006
Available online 19 June 2006
Abstract—A stereoselective synthesis of (+)-aspicilin is described. Regio- and stereoselective functionalization by intramolecular
participation of the sulfinyl group, ene reaction, and macrolactonization by Wadsworth–Emmons reaction employing Masa-
mune–Roush protocol are the key steps of the route.
Ó 2006 Elsevier Ltd. All rights reserved.
The polyhydroxylated macrocyclic lactone (+)-aspicilin
(1) was first isolated in 19001 by Hesse from Lecanora-
ceae family of lichen. Structure 1 was deduced by degra-
dational, spectroscopic,2 X-ray crystallographic and
synthetic studies.3 Though aspicilin has been reported
not to possess any biological activity, its unique struc-
ture with three contiguous chiral centers within an 18-
membered macrocyclic ring has attracted attention of
synthetic chemists and a number of elegant total synthe-
ses have been reported.4
sis of (+)-aspicilin. The synthetic route relied on macro-
cyclization by Wadsworth–Emmons reaction of the
aldehyde obtained from 2, itself readily derived from
bromodiol 3.
Bromodiol 3 is available by the reaction of unsaturated
sulfoxide 4 (>95% de) with NBS.6 The anti,syn-triol mo-
tif present in 1 required replacement of bromide by hy-
droxyl group with retention of configuration which was
achieved by two successive inversions. Thus subjecting
epoxide 5, obtained from bromohydrin 3 by treatment
25
with potassium carbonate (90%, ½aꢀD ꢁ88.9 (c 0.75,
OH OH
OH
P(O)(OEt)2
O
O
OTBS
OH
CHCl3)), to treatment with benzoic acid in the presence
of titanium tetraisopropoxide according to the Sharpless
O
protocol7 afforded regio- and stereoselectively benzoate
O
O
O
25
6 (55%, ½aꢀD ꢁ98.4 (c 0.8, CHCl3)) (Scheme 1) along
with small quantities of the corresponding sulfide (10%).
1
2
25
O
S
Conversion of 6 into the acetonide derivative (88%, ½aꢀD
OH Br
ꢁ69.9 (c 1, CHCl3)) followed by deprotection of the ester
O
25
p
-Tol
Bn
afforded alcohol 8 (91%, ½aꢀD ꢁ61.1 (c 1, CHCl3)). Selec-
OH
3
tive deprotection of the benzoate group after macrolact-
onization was expected to be difficult, necessitating an
alternate protecting group. Alcohol 8 was converted into
25
the corresponding t-butyldimethylsilyl ether 9 (89%, ½aꢀD
ꢁ72 (c 1, CHCl3)). Silyl ether 9 was treated with trifluoro-
acetic anhydride, the resulting intermediate 10 without
isolation was reacted with the terminal alkene8 11 and
We have recently reported on the use of the sulfinyl moi-
ety as an intramolecular nucleophile to functionalize
olefins activated by suitable electrophiles.5 We describe
herein an application of this methodology to the synthe-
tin tetrachloride to afford homoallylsulfide 129 (65%,
25
½aꢀD +12 (c 1, CHCl3)) (Scheme 2).
Hydrogenolysis of 12 using Raney-Ni afforded alcohol 2
Keywords: Aspicilin; Sulfinyl group; Ene reaction; Macrolactonization.
25
q IICT Communication No. 060308.
(80%, ½aꢀD +2.5 (c 1, CHCl3)). Oxidation of the primary
hydroxy group using Dess–Martin periodinane10 and
intramolecular Wadsworth–Emmons reaction of the
*
Corresponding author. Tel.: +91 040 27160123; fax: +91 040
27160512; e-mail: sraghavan@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.043

5596
S. Raghavan, T. Sreekanth / Tetrahedron Letters 47 (2006) 5595–5597
O
S
O
S
OH
OH Br
Ref. 6
K2CO3
MeOH
O
O
p-Tol
Bn
p
-Tol
Bn
OH
4
3
Ti(OiPr)4
O
S
O
S
OH
OH OC(O)Ph
O
PhCO2H
O
p
-Tol
Bn
p
-Tol
Bn
O
OH
5
6
Scheme 1.
OMe
OMe
O
OTBS
OP
O
O
O
(CF3CO)2O
CH2Cl2
S
O
S
p
-Tol
Bn
p
-Tol
Bn
6
Cat. CSA
CH2Cl2
O
O
CF3(O)CO
10
7, P = C(O)Ph
8, P = H
DIBAL-H, THF
TBS-Cl, Imidazole
CH2Cl2
9, P = TBS
P(O)(OEt)2
O
P(O)(OEt)2
O
O
OTBS
S
O
p
-Tol
11, SnCl4
OBn O
O
11
12
Scheme 2.
25
resulting aldehyde (90%, ½aꢀD +6.3 (c 1.5, CHCl3)) with
using bromodiol 3 readily obtained from methyl p-tolyl-
sulfoxide. The key steps include nucleophilic sulfinyl
group participation, ene reaction, and macrolactoniza-
tion using mild conditions.
the phosphonate ester employing Masamune–Roush
conditions11 yielded fully protected aspicilin 14 (60%,
25
½aꢀD ꢁ11.2 (c 1.0, CHCl3)). Smooth deprotection of 14
was achieved with aq methanolic HCl to provide the tar-
get12 (1) (Scheme 3) with spectroscopic and specific rota-
tion consistent with the reported value.4b
Acknowledgements
In summary, a stereoselective synthesis of the polyhydr-
oxylated natural product (+)-aspicilin has been achieved
S.R. is thankful to Dr. J. S. Yadav, Director, IICT, for
constant support and encouragement. T.S. is thankful to
OAc
AcO
OAc
I
P(O)(OEt)2
O
O
OTBS
OH
P(O)(OEt)2
O
O
OTBS
O
O
O
Raney-Ni
EtOH
O
12
O
O
O
CH2Cl2
2
13
O
OTBS
OH OH
OH
O
O
O
O
1M HCl, MeOH
LiCl, DBU
CH3CN
O
14
1
Scheme 3.

S. Raghavan, T. Sreekanth / Tetrahedron Letters 47 (2006) 5595–5597
5597
Durner, G. Tetrahedron Lett. 1991, 32, 7397; (l) Quinkert,
G.; Fernholz, E.; Eckes, P.; Durner, G. Helv. Chim. Acta
1989, 72, 1753; (m) Quinkert, G.; Heim, N.; Glenneberg,
J.; Doller, U.; Eichhorn, M.; Billhardt, U.-M.; Schwarz,
C.; Zimmerman, G.; Bats, J. W.; Durner, G. Helv. Chim.
Acta 1988, 71, 1719; (n) Waanders, P. P.; Thijs, L.;
Zwanenburg, B. Tetrahedron Lett. 1987, 28, 2409.
5. (a) Raghavan, S.; Sreekanth, T. Tetrahedron: Asymmetry
2004, 15, 565; (b) Raghavan, S.; Ramakrishna Reddy, S.
Tetrahedron Lett. 2004, 45, 5593.
6. Raghavan, S.; Rajender, A.; Yadav, J. S. Tetrahedron:
Asymmetry 2003, 14, 2093.
7. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50,
1560.
8. The terminal alkene 11 was readily prepared from 1-
decenal following the sequence indicated. For hydrolytic
kinetic resolution refer (a) Tokunaga, M.; Larrow, J. F.;
Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936; (b)
Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001,
123, 2687; (c) Breinbauer, R.; Jacobsen, E. N. Angew.
Chem., Intl. Ed. 2000, 39, 3604.
CSIR, New Delhi, for a fellowship. Financial assistance
from DST (New Delhi) is gratefully acknowledged. We
thank Dr. A. C. Kunwar for the NMR spectra and
Dr. M. Vairamani for the mass spectra.
References and notes
1. (a) Hesse, O. J. Prakt. Chem. 1900, 62, 430; (b) Hesse, O.
J. Prakt. Chem. 1904, 70, 449.
2. Huneck, S.; Schreiber, K.; Steglich, W. Tetrahedron 1973,
29, 3687.
3. Quinkert, G.; Heim, N.; Bats, J. W.; Oschkinat, H.;
Kessler, H. Angew. Chem., Int. Ed. Engl. 1985, 24,
987.
4. (a) Banwell, M. G.; Mcrae, K. J. Org. Lett. 2000, 2, 3583;
(b) Maezaki, N.; Li, Y.-X.; Ohkubo, K.; Goda, S.; Iwata,
C.; Tanaka, T. Tetrahedron 2000, 56, 4405; (c) Dixon, D.
J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123; (d)
Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K.
O
O
Me3S I
NaH, DMSO, THF
94%
a
b
O
PO
LAH
90%
(R,
R)-salen Co(III)OAc
45%
DCC
HO2C
c
d, P = H
92%
11, P = C(O)CH2P(O)(OEt)2
94% d.e
(EtO)2(O)P
J. Org. Chem. 1998, 63, 7505; (e) Nishioka, T.; Iwabuchi,
Y.; Irie, H.; Hatakeyama, S. Tetrahedron Lett. 1998, 39,
5597; (f) Chenevert, R.; Lavoie, M.; Dasser, M. Can. J.
Chem. 1997, 75, 68; (g) Sinha, S. C.; Keinan, E. J. Org.
Chem. 1997, 62, 377; (h) Enders, D.; Prokopenko, O. F.
Liebigs Ann. 1995, 1185; (i) Oppolzer, W.; Radinov, R. N.;
de Brabander, J. Tetrahedron Lett. 1995, 36, 2607; (j)
Solladie, G.; Fernandez, I.; Maestro, C. Tetrahedron:
Asymmetry 1991, 2, 801; (k) Quinkert, G.; Becker, H.;
9. Ishibashi, H.; Komatsu, H.; Ikeda, M. J. Chem. Res. (S)
1987, 296. The configuration of the new streogenic center
was not established.
10. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4155.
11. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A.
P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
Lett. 1984, 25, 2183.
12. About 30% of dimer (oligomer) also formed.