Enantioselective total synthesis of macrolide antitumor agent (-)-lasonolide A

Article abstract of DOI:10.1021/ol0701013

Equation presented An enantioselective total synthesis of (-)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahy

Full text of DOI:10.1021/ol0701013

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1437-1440
Enantioselective Total Synthesis of
Macrolide Antitumor Agent
(−)-Lasonolide A
Arun K. Ghosh* and Gangli Gong
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907
akghosh@purdue.edu
Received January 14, 2007
ABSTRACT
An enantioselective total synthesis of (−)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an
intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahydropyran ring as well as the quaternary stereocenter
present in the molecule. The lower tetrahydropyran ring was assembled by a catalytic asymmetric hetero-Diels
Three stereocenters were enantioselectively installed in this single step reaction.
−Alder reaction as the key step.
Marine natural products continue to provide structurally
diverse molecules with intriguing biological properties. Many
such molecules exhibit potent antitumor activity; however,
the scarcity of natural abundance often limits their subsequent
biological studies.1 Lasonolide A (1), a 20-membered mac-
rolide, was isolated from the Caribbean marine sponge,
Forcepia sp., by McConnell and co-workers in 1994.2 Since
then, a series of other lasonolides with potent antitumor
properties were isolated. Lasonolide A remains to be the most
potent of the series with IC50 values of 8.6 and 89 nM against
A-549 human lung carcinoma and Panc-1 human pancreatic
carcinoma, respectively.2 The initial structural and stereo-
chemical assignment of lasonolide A was established by
extensive NMR studies. Its structure and absolute stereo-
chemistry were later revised through total synthesis3a and
subsequent biological studies by Lee and co-workers.3b
Lasonolide A’s structural features as well as its potent
antitumor activities attracted considerable synthetic interest.
Thus far, three total syntheses3-5 and a number of synthetic
studies on both tetrahydropyran rings6 have been reported.
Herein we report an enantioselective total synthesis of (-)-
lasonolide A (1).
The retrosynthetic analysis is outlined in Figure 1. La-
sonolide A (1) can be disconnected at C25-C26 into side
chain fragment phosphonium salt 2 and the 20-membered
(4) (a) Kang, S. H.; Kang, S. Y.; Choi, H.; Kim, C. M.; Jun, H.; Youn,
J. Synthesis 2004, 7, 1102. (b) Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi,
H.; Jun, H.; Lee, B. M.; Park, C. M.; Jeong, J. W. Angew. Chem., Int. Ed.
2003, 42, 4779.
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Shishido, K. Org. Lett. 2006, 8, 475.
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Nowakowski, M.; Hoffmann, H. M. R. Tetrahedron Lett. 1997, 38, 1001.
(c) Beck, H.; Hoffmann, H. M. R. Eur. J. Org. Chem. 1999, 2991. (d)
Gurjar, M. K.; Kumar, P.; Venkateswara Rao, B. Tetrahedron Lett. 1996,
37, 8617. (e) Gurjar, M. K.; Chakrabarti, A.; Venkateswara Rao, B.; Kumar,
P. Tetrahedron Lett. 1997, 38, 6885. (f) Dalgard, J. E.; Rychnovsky, S. D.
Org. Lett. 2005, 7, 1589. (g) Sawant, K. B.; Ding, F.; Jennings, M. P.
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(1) Harris, C. R.; Danishefsky, S. J. Org. Chem. 1999, 64, 8434.
(2) Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J.
Am. Chem. Soc. 1994, 116, 6015.
(3) (a) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Joo,
J. M. J. Am. Chem. Soc. 2002, 124, 384. (b) Song, H. Y.; Joo, J. M.; Kang,
J. W.; Kim, D. S.; Jung, C. K.; Kwak, H. S.; Park, J. H.; Lee, E.; Hong, C.
Y.; Jeong, S.; Jeon, K.; Park, J. H. J. Org. Chem. 2003, 21, 8080.
10.1021/ol0701013 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/17/2007

the corresponding aldehyde with nitromethane afforded nitro
alcohol 12 as a diastereomeric mixture. The newly generated
stereocenter was eliminated by converting 12 into the
corresponding nitroalkene with MsCl and Et3N. Reduction
of the resulting nitroalkene using Zn and AcOH provided
oxime 13.
Scheme 1. Enantioselective Synthesis of Oxime 13
Figure 1. Retrosynthetic analysis of lasonolide A.
macrolide core 3 containing tetrahydropyrans A and B.
Further disconnection of macrolactone 3 would lead to
sulfone 4 and aldehyde 5. Assembly of the macrocycle would
proceed through Julia-Kocienski coupling7 between 4 and
5 at the C14-C15 and subsequent intramolecular Horner-
Wadsworth-Emmons reaction at C2-C3. Fragment contain-
ing ring A (4) would be built through an intramolecular
[3+2] nitrile oxide cycloaddition. Construction of ring B (5)
containing fragment could be efficiently achieved from the
asymmetric chromium-catalyzed hetero-Diels-Alder reac-
tion.8
The synthesis of ring A started with the known aldehyde
69 as shown in Scheme 1. Isopropenyl magnesium bromide
was added to aldehyde to form racemic allylic alcohol rac-7
in 94% yield. Kinetic resolution utilizing Sharpless asym-
metric epoxidation10 provided the desired optically pure
alcohol (-)-(S)-7 in 45% yield and 98% ee. The known
epoxide 810 was converted to its corresponding tosylate 9.
Regioselective epoxide opening of 9 with alcohol 7 in the
presence of catalytic BF3•OEt2 provided ether 10 according
to the Hoffmann protocol.11 Treatment of alcohol tosylate
10 with K2CO3 afforded the corresondong epoxide, which
was converted to diol 11 by treatment with aqueous HClO4.
Oxidative cleavage of diol 11 followed by condensation of
Exposure of 13 to sodium hypochlorite led to facile
intramolecular 1,3-dipolar cycloaddition via the nitrile oxide
to afford isoxazoline 14 as a single diastereomer (Scheme
2).12 The quaternary stereocenter at C22 was constructed
efficiently at the same time as forming the tetrahydropyran
ring. Raney-nickel catalyzed hydrogenolysis of isooxazoline
14 provided â-hydroxy ketone 15.13 L-Selectride reduction
of the ketone provided the corresponding axial alcohol. The
resulting diol was protected as acetonide 16 in 87% yield in
two steps. Both benzyl groups of 16 were removed by
catalytic hydrogenation to provide diol. The diol was then
protected as bis-TBS-ether 17. Exposure of 17 to TBAF
provided desired alcohol 18 in 40% yield along with
recovered 17 (32%) and the corresponding diol (24%), which
was converted to 17. Alcohol 18 was obtained in 62% yield
after one recycle. Dess-Martin oxidation14 of 18 followed
by Wittig reaction afforded olefin, which was treated with
TBAF to give alcohol 19. Cross metathesis between olefin
19 and sulfone 2015 in the presence of second generation
Grubbs’ catalyst16 provided olefin 21 in 81% yield.17 Alcohol
(7) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175. (b) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley,
A. Synlett 1998, 1, 26.
(8) (a) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398. (b) Gademann, K.; Chavez, D. E.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2002, 41, 3059.
(9) Hon, Y.; Lu, L.; Chang, R.; Lin, S.; Sun, P.; Lee, C. Tetrahedron
2006, 56, 9269.
(10) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(11) Hoffmann, H. M. R.; Brandes, A. Tetrahedron 1995, 51, 155.
(12) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
(13) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(15) See the Supporting Information for details.
(16) Scholl, M.; Ding, S.; Lee, C.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
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Org. Lett., Vol. 9, No. 8, 2007

21 was protected with benzoyl peroxide and Me2S to provide
MTM ether 4 in 88% yield.18
olefin 30 in 68% yield. Alcohol 30 was oxidized to the
corresponding aldehyde under Dess-Martin conditions.
Horner-Wadsworth-Emmons olefination of the above al-
dehyde with ethyl 2-[di(o-isopropylphenyl)phosphono] pro-
pionate under Ando’s conditions22 provided the trisubstituted
Z-olefin 31 in 71% yield for 2 steps. DIBAL reduction of
ester 31 followed by Dess-Martin oxidation gave aldehyde
5 in 91% yield for 2 steps.
Scheme 2. Stereoselective Synthesis of 4
Scheme 3. Stereoselective Synthesis of Fragment 5
The synthesis of the lower tetrahydropyran ring B of
lasonolide A is shown in Scheme 3. The chiral tridentate
Schiff base chromium(III) complex (1S,2R)-24 developed by
Jacobsen8 was used as catalyst (10 mol %) in the asymmetric
hetero-Diels-Alder reaction between diene 2219 and alde-
hyde 23.20 The resulting dihydropyran silyl enol ether was
treated with TBAF/AcOH in the same pot to remove the
TES group and give the corresponding ketone 25 in 71%
yield and 94% ee.21 Reduction of the ketone with Dibal-H
gave axial alcohol 26 and equatorial alcohol 27 as a 1:2
separable mixture in 96% combined yield. Among all the
other reducing agents we tried, including L-Selectride,
NaBH4, DIBAL, Red-Al, LiEt3BH, SmI2, and BH3, the
undesired equatorial hydroxy pyran 27 was always the
predominant product. Therefore, we recycled 27 back to 26
using Swern oxidation followed by reduction. Protection of
the secondary alcohol with TBSOTf, debenzylation under
Pd/H2, Dess-Martin oxidation of the corresponding alcohol
and following Wittig reaction furnished the olefin, of which
the primary TBS group was selectively removed with CSA
to afford alcohol 28 in 71% yield over 5 steps. Cross
metathesis between olefin 28 and bis-TBS-butene 29 in the
presence of second generation Grubbs’ catalyst provided
The final stages for assembly of lasonolide A are illustrated
in Scheme 4. Sulfone 4 and aldehyde 5 were coupled under
Scheme 4. Synthesis of Macrolide 2
(17) Chatterjee, A. K.; Choi, T.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(18) Medina, J. C.; Salomon, M.; Kyler, K. S. Tetrahedron Lett. 1988,
29, 3773.
(19) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A.
Tetrahedron 1996, 52, 2167.
(20) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; O’Brien,
M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70, 150.
(21) The ee was determined by 19F NMR of the Mosher ester of 27.
Julia-Kocienski conditions7 to provide tetraene 32 in 78%
yield. Acetonide and primary TBS groups were removed by
(22) Ando, K. J. Org. Chem. 1998, 63, 8411.
Org. Lett., Vol. 9, No. 8, 2007
1439

CSA to give triol. The two primary hydroxy groups were
then protected with TBSCl. The secondary alcohol was
converted to phosphonoacetate by using DCC and DMAP.
The less hindered allylic primary TBS group was removed
by PPTS to provide the hydroxy phosphonoacetate 33. Dess-
Martin oxidation of alcohol 33 followed by intramolecular
Horner-Wadsworth-Emmons olefination furnished mac-
rolactone 3 in 62% yield for 2 steps.
Wittig olefination with 2-derived phosphorane afforded the
TBS-protected lasonolide A 38. Final global TBS-deprotec-
tion with HF‚Py in the presence of excess pyridine furnished
(-)-lasonolide A (1, [R]23 -24 (c 0.37, CDCl3)). The
D
spectroscopic data of synthetic lasonolide A (1) are identical
with those of the natural product.2
Scheme 6. Synthesis of (-)-Lasonolide A
Preparation of phosphonium salt 2 was carried out as
shown in Scheme 5. Commercially available acid 34 was
Scheme 5. Synthesis of Phosphonium Salt 2
In summary, we have reported an asymmetric total
synthesis of (-)-lasonolide A. The two key highly substituted
tetrahydropyran fragments of lasonolide A were synthesized
in enantiomerically pure form. The upper tetrahydropyran
ring was constructed by an intramolecular 1,3-dipolar cy-
cloaddition via nitrile oxide to bicyclic isoxazoline with
stereoselective building of the quaternary center. The lower
tetrahydropyran ring was assembled by a catalytic asym-
metric hetero-Diels-Alder reaction while setting three ste-
reocenters enantioselectively at the same time. The synthesis
also features Lewis acid-catalyzed opening of epoxide to
stereoselectively form substituted ether, efficient cross me-
tathesis of functionalized olefins, and the intramolecular
Horner-Emmons reaction. Eight of the nine chiral centers
were derived through asymmetric synthesis. The present
synthesis will provide access to a variety of structural
analogues of lasonolide A for biological studies.
converted to the corresponding Weinreb amide. DIBAL
reduction of the amide provided aldehyde. Methylenation
of the resulting aldehyde with Eschenmoser’s salt,23 followed
by reduction of the resulting aldehyde with LAH provided
allylic alcohol 35 in 63% yield for 4 steps. Esterification of
known acid 3624 with alcohol 35 gave the corresponding
ester, which was converted to bis-TBS-ether 37 by depro-
tection of the benzylidene group followed by protection of
the resulting diol as TBS-ethers. Phosphonium salt 2 was
prepared from 37 as described previously.3
Acknowledgment. Financial support for this work was
provided in part by the National Institutes of Health and
Purdue University.
Synthesis of lasonolide A was carried out from macro-
lactone 3 as shown in Scheme 6. Removal of the MTM group
25
was achieved by exposure to HgCl2 in the presence of
CaCO3 in aqueous acetonitrile. Dess-Martin oxidation of
the resulting alcohol provided the corresponding aldehyde.
Supporting Information Available: Experimental pro-
cedures, spectral data for compounds, and 1H NMR and 13
C
NMR spectra for 1, 3-5, 10-12, 14, 15, 19, 21, 25, 26,
and 30-33. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. 1971, 10, 330.
(24) Ma, X.; Saksena, R.; Chernyak, A.; Kovac, P. Org. Biomol. Chem.
2003, 1, 775.
(25) Corey, E. J.; Bock, M. J. Tetrahedron Lett. 1975, 16, 3269.
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