Synthesis of the C1-C9 fragment of callipeltoside-A

Article abstract of DOI:10.1021/ol006003y

(Equation presented) The C1-C9 fragment of callipeltoside (17) was prepared in 12 steps and 7.2% overall yield from bicyclic lactone (+)-4. Key steps include a stereoselective epoxidation and further regiocontrolled nucleophilic opening of the oxirane ring to install two vicinal stereocenters (C5 and C6), and the use of bis(trimethylsilyl) peroxide and a catalytic amount of Sn(IV) chloride for the chemoselective Baeyer-Villiger oxidation of unsaturated cyclopentanone 15.

Full text of DOI:10.1021/ol006003y

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1931-1933
Synthesis of the C1−C9 Fragment of
Callipeltoside-A†
Francisco Vela´zquez and Horacio F. Olivo*
DiVision of Medicinal and Natural Products Chemistry, College of Pharmacy,
and The Center for Biocatalysis and Bioprocessing, The UniVersity of Iowa,
Iowa City, Iowa 52242
horacio-oliVo@uiowa.edu
Received May 1, 2000
ABSTRACT
The C1−C9 fragment of callipeltoside (17) was prepared in 12 steps and 7.2% overall yield from bicyclic lactone (+)-4. Key steps include a
stereoselective epoxidation and further regiocontrolled nucleophilic opening of the oxirane ring to install two vicinal stereocenters (C5 and
C6), and the use of bis(trimethylsilyl) peroxide and a catalytic amount of Sn(IV) chloride for the chemoselective Baeyer−Villiger oxidation of
unsaturated cyclopentanone 15.
Three macrocyclic lactones possessing the same aglycon
skeleton and bearing different sugars, callipeltosides A-C,
were isolated from the marine lithistid sponge Callipelta sp.
by Minale and collaborators in 1996.1 Callipeltoside A (1)
was found to inhibit in vitro proliferation of KB and P388
cells and to protect cells infected with HIV virus. The relative
configuration of this complex macrolactone containing a
hemiketal ring and adorned with a unique dienyne-trans-
chlorocyclopropyl side chain and a deoxyaminosugar moiety
was deduced by extensive 2D NMR experiments (absolute
stereochemistry not determined). We are engaged in an
enantioselective synthesis of this molecule to confirm the
relative configuration, determine the absolute stereochem-
istry, and provide sufficient amounts for further biological
studies.
In planning our synthesis of callipeltoside, we envision a
convergent synthesis that leads to fragments 2 and 3 through
cleavage of the macrolide linkage (C1-O-C13) and the C9-
C10 vinylic bond (Scheme 1). In the synthetic direction,
Scheme 1
The complex structure of this natural product has already
motivated some synthetic efforts. The synthesis of the
aminosugar callipeltose was reported by Giuliano and co-
workers.2 Hoye and Zhao recently reported their attempts
to cyclize the C1-C14-containing fragment of callipeltoside.3
linkage of aldehyde 2 and vinyl iodide 3 will be ac-
complished via a Ni(II)/Cr(II)-mediated coupling reaction4
followed by macrolactonization. We envisioned the construc-
tion of the hemiketal framework (C1-C9) of callipeltoside
starting from bicyclic lactone (+)-4.
† Dedicated to Prof. Tomas Hudlicky on occasion of his 50th birthday.
(1) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc. 1996, 118, 11085-11088. (b) Zampella, A.; D’Auria,
M. V.; Minale, L.; Debitus, C. Tetrahedron 1997, 53, 3243-3248.
10.1021/ol006003y CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/03/2000

Bicyclic lactone 4 is readily available in multigram scale5
and has been prepared enantioselectively using microbial
Baeyer-Villiger oxidations6 and by recrystallization of
diasteromeric salts.7 Interestingly, oxidation of bicyclo[3.2.0]-
hept-5-en-2-one (5) with Acinetobacter sp. (NCIB 9872)
produces the enantiomer (-)-4,6b while oxidation with
Pseudomonas putida (NCIB 10007) produces the enantiomer
(+)-4, Scheme 2.6c Lactone 4 has proved to be a useful
unsaturated lactone 7 using peracetic acid in a mixture of
sodium acetate-acetic acid gave preferentially the endo-
epoxide 8.8a Protection of the lactone moiety of compound
8 was required before the nucleophilic opening of the oxirane
ring. Epoxylactol 9 was obtained as a mixture of stereoiso-
mers, which were smoothly converted to the corresponding
methyl acetal 10 when reacted with methanol in the presence
of Dowex ion-exchange resin.9
Regioselective nucleophilic opening of the oxirane ring
of compound 10 with Gilman’s reagent at low temperature
gave the desired alcohol 11 as the major product (16:1 ratio
of regioisomers), Scheme 4. Protection of the hindered
Scheme 2
Scheme 4a
intermediate for the synthesis of prostaglandins8 and
monoterpenes.5a Lactone 4 has also been used to prepare
tetrasubstituted δ-lactones via oxidation of cyclopentanones
with m-chloroperoxybenzoic acid (m-CPBA).9 This strategy
appears very attractive to prepare a large variety of substi-
tuted δ-lactones with a high degree of stereocontrol, but it
is limited to compounds lacking unsaturations. To overcome
this problem, we were interested in enlarging a cyclopen-
tanone ring possessing an unsaturated substituent using a
chemospecific Baeyer-Villiger oxidation.10 We report in this
letter a stereoselective synthesis of the C1-C9 fragment of
callipeltoside from bicyclic lactone (+)-4.
a (a) MeLi, CuI, Et2O, - 78 °C to - 30 °C, 5 h; (b) PMBCl,
NaH, n-Bu4NI, DMF-THF, rt, 40 h; (c) concd HCl, THF/H2O (2:
1), 40 °C, 2 h; (d) PPh3dCH2, 40 °C, THF, 12 h; (e) cat. TPAP,
NMO, 4 Å molecular sieves, CH2Cl2, 12 h.
Alkylation of lactone (+)-4 with methyl iodide provided
compound 6, Scheme 3. Kinetic protonation of the lithium
hydroxyl group of compound 11 as its p-methoxybenzyl ether
12 was accomplished in high yield using p-methoxybenzyl
chloride in the presence of tetrabutylammonium iodide.
Deprotection of methyl acetal 12 under acidic conditions
furnished lactol 13. Olefination with methylenetriphenylphos-
phorane did not proceed at room temperature but required
warming to 40 °C to deliver unsaturated alcohol 14.
Scheme 3a
(2) Smith, G. R.; Finley IV, J. J.; Giuliano, R. M. Carbohydr. Res. 1998,
308, 223-227.
(3) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 169-171.
(4) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281-5284. (b) Jin, H.; Uenishi, J.; Christ,
W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644-5646.
(5) (a) Grieco, P. A. J. Org. Chem. 1972, 37, 2363-2364. (b) Minns,
R. A. Organic Syntheses; Wiley: New York, 1973; Collect. Vol. VI, pp
1037-1040.
(6) (a) Alphand, V.; Archelas, A.; Furstoss, R. Tetrahedron Lett. 1989,
30, 3663-3364. (b) Carnell, A. J.; Roberts, S. M.; Sik, V.; Willets, A. J.
J. Chem. Soc., Perkin Trans. 1 1991, 2385-2389. (c) Grogan, G.; Roberts,
S. M.; Willets, A. J. J. Chem. Soc., Chem. Commun. 1993, 699-701.
(7) Corey, E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832-6833.
(8) (a) Corey, E. J.; Noyori, R. Tetrahedron Lett. 1970, 311-313. (b)
Corey, E. J.; Nicolaou, K. C.; Beames, D. J. Tetrahedron Lett. 1974, 2439-
2440. (c) Newton, R. F.; Roberts, S. M. Tetrahedron 1980, 36, 2163-2196.
(9) Clissold, C.; Kelly, C. L.; Lawrie, K. W. M.; Willis, C. L. Tetrahedron
Lett. 1997, 38, 8105-8108.
a (a) LHMDS, MeI, - 78 °C, THF, 1.5 h; (b) LHMDS, - 78
°C, 2 h; then aq NH4Cl; (c) AcOOH (1.5 equiv), NaOAc (2.0 equiv),
HOAc, rt, 48 h; (d) DIBAL-H, toluene-CH2Cl2, - 78 °C, 3 h; (e)
MeOH, Dowex-50, rt, 4 h.
(10) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett 1997,
971-973.
enolate of lactone 6 gave the thermodynamically unfavored
methyl lactone 7. We found that the workup procedure in
the epimerization step was critical in the stereochemical
outcome of the reaction.11 Stereoselective epoxidation of
(11) The epimerization step was previously reported to give isomers 6:7
in a 4.7: 1 ratio, 15% yield of 7.6b We found that transferring the enolate
solution into the organic phase to a 1:1 mixture of sat. solution of ammonium
chloride-ether, and vigorous mixing leads to better yield (78%) and ratio
of isomers 6:7 (1:17). See Supporting Information for a detailed procedure.
1932
Org. Lett., Vol. 2, No. 13, 2000

Oxidation of alcohol 14 with tetrapropylammonium perru-
thenate and N-methylmorpholine N-oxide yielded ketone
15.12
contiguous chiral centers and the hemiketal framework of
the natural product.
In summary, we have prepared an advanced intermediate
for the synthesis of the macrocyclic lactone of callipeltoside,
starting from biocatalytically generated bicyclic lactone 4.
Gilman’s reagent was highly regioselective and efficient in
the nucleophilic opening of epoxide 10 to construct the
vicinal stereocenters C5 and C6. The use of BTSP and Sn-
(IV) chloride proved to be an effective procedure to enlarge
a functionalized cyclopentanone containing an unsaturation.
The synthesis of the C10-C22 southern fragment 3 and the
synthesis of 1 will be reported in due time.
Baeyer-Villiger oxidation of cyclopentanone 15 using
hydrogen peroxide under acidic conditions gave the desired
δ-lactone 16 in low yield (<30%) after 48 h. Oxidation of
cyclopentanone 15 with m-CPBA gave also the desired
δ-lactone 16 in 50-60% yield, 10-20% of starting material,
and a small amount of mixture of epoxylactones.13 Thus,
we selected Shibasaki’s protocol,10 recently employed in his
elegant synthesis of epothilone.14 Oxidative ring expansion
using bis(trimethylsilyl) peroxide (BTSP), a catalytic amount
of Sn(IV) chloride, and trans-diaminocyclohexane gave the
desired δ-lactone 16 in 78% yield, in which the terminal
alkene remained intact (Scheme 5). Addition of the lithium
Acknowledgment. This work was supported by a grant
from the National Science Foundation (CHE-99-74384), and
the Central Investment Fund for Research Enhancement at
The University of Iowa. We thank Consejo Nacional de
Ciencia y Tecnolog´ıa (CONACyT, Me´xico) for a predoctoral
fellowship to F.V.
Scheme 5a
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra for compounds 6-17. This information is available
free of charge via the Internet at http://pubs.acs.org.
OL006003Y
a (a) Bis(trimethylsilyl) peroxide, cat. SnCl4, 4 Å molecular
sieves, 1,2-diaminocyclohexane, CH2Cl2, 0 °C to room temperature,
48 h; (b) EtOAc, LHMDS, THF, - 78 °C to 0 °C, 2 h.
(12) (a) Sharpless, K. B.; Akashi, K.; Oshima, K. Tetrahedron Lett. 1976,
29, 2503-2506. (b) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White,
A. D. J. Chem. Soc., Chem. Commun. 1987, 1625-1627.
(13) N. Ouvrard, J. Rodriguez, M. Santelli. Tetrahedron Lett. 1993, 34,
1149-1150.
(14) Sawada, D.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 209-
213.
(15) Dugan, A. J.; Adams, M. A.; Brynes, P. J.; Meinwald, J. Tetrahedron
Lett. 1978, 45, 4323-4326.
enolate of ethyl acetate to lactone 16 gave the desired
hemiketal 17.15 Compound 17 is an advanced intermediate
for the synthesis of callipeltoside, which contains four
Org. Lett., Vol. 2, No. 13, 2000
1933