Enantioselective Total Synthesis of (+)-Leucascandrolide A Macrolactone

Article abstract of DOI:10.1021/ol035797o

(Matrix presented) The enantioselective synthesis of the (+)-leucascandrolide A macrolactone has been achieved in 20 linear steps from 1,3-propanediol. The key steps in the synthesis are a reductive cleavage of bicyclic ketal 5 to establish the C15 stereo

Full text of DOI:10.1021/ol035797o

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4641-4644
Enantioselective Total Synthesis of
(+)-Leucascandrolide A Macrolactone
Michael T. Crimmins* and Phieng Siliphaivanh
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received September 17, 2003
ABSTRACT
The enantioselective synthesis of the (+)-leucascandrolide A macrolactone has been achieved in 20 linear steps from 1,3-propanediol. The
key steps in the synthesis are a reductive cleavage of bicyclic ketal 5 to establish the C15 stereogenic center and a diastereoselective aldol
of the boron enolate of methyl ketone 3 to aldehyde 4 in preparation for a heteroconjugate addition for the introduction of the C3 stereocenter.
Leucascandrolide A (1) was isolated by Pietra and co-
workers in 1996 from the calcareous sponge Leucascandra
caVeolata collected from the Coral Sea off the coast of New
Caladonia.1 The gross structure and relative stereochemistry
were assigned on the basis of extensive two-dimensional
NMR experiments, and the absolute configuration of the C5
stereocenter was assigned by Mosher ester analysis of the
macrolactone. Leucascandrolide A displayed significant in
vitro cytotoxicity (IC50 ) 0.05 and 0.25 µg/mL with KB
and P388 cells, respectively), as well as significant antifungal
properties. Additional attempts to isolate leucascandrolide
A from the sponge have proven unsuccessful,2 and thus the
full biological potential of the compound has not been
established. Consequently, leucascandrolide A has attracted
the interest of numerous synthetic groups;3,4 the first total
synthesis was reported by Leighton and co-workers in 2000.5
A (1) would be derived from the macrolactone 2 by
attachment of the oxazole-containing side chain at the C5
hydroxyl.3,4 The key C7 stereocenter of the macrolactone
would be established through a diasteroselective boron aldol
between methyl ketone 3 and aldehyde 4.6 Methyl ketone 3
containing the trans-2,6-disubstituted-tetrahydropyran would
be obtained from a stereoselective reductive cleavage of
bridged ketal 5.7 The bridged ketal would be derived from
a Horner-Wadsworth-Emmons reaction between aldehyde
6 (Scheme 3) and ketone phosphonate 7 (Scheme 2).
(4) Wipf, P.; Graham, T. H. J. Org. Chem. 2001, 66, 3242-3245.
Kozmin, S. A. Org. Lett. 2001, 3, 755-758. Kopecky, D. J.; Rychnovsky,
S. D. J. Am. Chem. Soc. 2001, 123, 8420-8421. Wang, Y.; Janjic, J.;
Kozmin, S. A. J. Am. Chem. Soc. 2002, 124, 13670-13671. Dakin, L. A.;
Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812-6815. Wipf,
P.; Reeves, J. T. Chem. Commun. 2002, 2066-2067. Fettes, A.; Carreira,
E. M. Angew. Chem., Int. Edit. 2002, 41, 4098-4101. Paterson, I.; Tudge,
M. Angew. Chem., Int. Ed. 2003, 42, 343. Paterson, I.; Tudge, M.
Tetrahedron 2003, 59, 6833-6849. Williams, D. R.; Plummer, S. V.;
Patnaik, S. Angew. Chem., Int. Ed. 2003, 42, 3934-3938.
Our retrosynthetic analysis for the total synthesis of leu-
cascandrolide A is illustrated in Scheme 1. Leucascandrolide
(5) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem.
Soc. 2000, 122, 12894-12895.
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51-60.
(6) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788.
Evans, D. A.; Coˆte´, B.; Coleman, P. J.; Connell, B. T. J. Am. Chem. Soc.
2003, 125, 10893-10898.
(2) D’Ambrosio, M.; Tato, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F. HelV.
Chim. Acta 1999, 82, 347-353.
(7) Kotsuki, H. Synlett 1992, 97-106. Ishihara, K.; Mori, A.; Yamamoto,
H. Tetrahedron 1990, 46, 4595-4612. Bogaczyk, S.; Brescia, M. R.;
Shimshock, Y. C.; DeShong, P. J. Org. Chem. 2001, 66, 4352-4355.
(3) Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2,
597-599.
10.1021/ol035797o CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/29/2003

Synthesis of the â-keto phosphonate 7 was completed as
outlined in Scheme 2. Addition of the titanium enolate of
acetyl thiazolidinethione 9 to aldehyde 8 gave 10 in high
yield as a 93:7 mixture of diastereomers.9 The diastereomeric
aldol adducts were readily separated10 by flash chromatog-
raphy and the major diastereomer was obtained in 67%
purified yield. Subsequent protection of the alcohol as a silyl
ether delivered TBS ether 11 in 93% yield. The thiazoli-
dinethione auxiliary was directly displaced with the anion
of methyl dimethylphosphonate providing the desired phos-
phonate 7 in excellent yield.
Scheme 1. Retrosynthesis of Leucascandrolide A (1)
The aldehyde required for the Horner-Wadsworth-
Emmons reaction with phosphonate 7 was constructed as
illustrated in Scheme 3. The known aldehyde 12 is easily
Scheme 3. Preparation of Aldehyde 6
accessible in 2 steps from 1,3-propanediol. Treatment of
aldehyde 12 according to the Brown protocol afforded
alcohol 13. Exposure of PMB ether 13 to DDQ in dichloro-
methane under anhydrous conditions provided the 1,3-PMP
acetal, and subsequent oxidative cleavage of the terminal
olefin delivered the desired aldehyde 6.11
The synthesis of the remaining C1-C7 fragment 4
(Scheme 4) began with the alkylation of TBS-protected
glycolate 15 with allyl iodide to give 16 (>98:2 dr).12
Reductive removal of the chiral auxiliary and a cross
metathesis13 of the resultant alcohol 17 with methyl acrylate
using Grubb’s second generation catalyst provided the R,â
unsaturated ester 18 in good yield. Alcohol 17 was oxidized
to aldehyde 19 followed by a one-carbon homologation via
methoxymethylene Wittig and treatment with mercuric(II)
acetate resulting in the desired aldehyde 4.
Aldehyde 6 could be obtained easily through the well-
established Brown crotylation8 of 3-p-methoxybenzyloxy-
propanal. The phosphonate fragment 7 could be derived
through a thiazolidinethione acetate aldol between the R,â
unsaturated aldehyde 8 and acetyl thiazolidinethione 9.
Scheme 2. Preparation of â-Ketophosphonate 7
The assembly of the three key fragments began by
execution of a Horner-Wadsworth-Emmons coupling
(8) Brown, H. C.; Bhat, R. S.; Liao, Y.; Khanna, V. V. J. Am. Chem.
Soc. 1986, 108, 5919-5923.
(9) Gonza´lez, AÄ ; Aiguade´, J.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett.
1996, 37, 8949-8952. Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999,
1, 2029-2032.
(10) N-Acylthiazolidinethiones are bright yellow, resulting in the ability
to follow the chromatography visually as the two yellow bands pass down
the column.
(11) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478-479.
(12) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165-2167.
(13) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783-3784.
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Org. Lett., Vol. 5, No. 24, 2003

of the desired trans isomer. Thus, the internal delivery of
the coordinated reducing agent in the reduction of 5 provided
the desired trans 2,6-tetrahydropyran as a 15:1 mixture of
diastereomers.
Scheme 4. Synthesis of Aldehyde 4
Scheme 5. Completion of Methyl Ketone 3
between ketophosphonate 7 and aldehyde 6 under Paterson’s
conditions with barium hydroxide to deliver enone 20 in
excellent yield.14 At this point, it was necessary to selectively
reduce the enone double bond. While NaBH4-NiCl2 cleanly
reduced the enone,15 varying amounts (10-20%) of reduction
of the C18-C19 isolated olefin always accompanied enone
reduction. After a brief survey of conditions, it was found
that the enone double bond could be selectively reduced with
i-Bu2AlH in THF in the presence of HMPA to give the
saturated ketone 21 in 87% yield with no evidence of over
reduction of the ketone.16 Attempts to directly access the
bridged ketal 5 from 21 under acid catalysis resulted in
significant decomposition. Therefore, a two-step protocol was
adopted, wherein the PMP benzylidine was first treated with
PPTS in methanol to give the mixed methyl ketal. Upon
further treatment with PPTS in dichloromethane, methanol
was lost to provide the desired bicyclic ketal 5. Treatment
of 5 with i-Bu2AlH under the conditions described by
Kotsuki smoothly delivered the tetrahydropyran 22 in 93%
yield presumably through the intramolecular delivery of
hydride by coordination of i-Bu2AlH to the ketal oxygen.6
Unfortunately, the desired 2,6-trans tetrahydropyran was
inseparable from its 2,6-cis isomer and their ratio could not
With both methyl ketone 3 and aldehyde 4 in hand, it was
possible to explore the assembly of the two subunits through
a double diastereoselective aldol reaction. On the basis of
precedent from studies by Evans6 and examples from our
own synthesis of spongistatin,17 as well as other recent
examples,18 we anticipated a highly selective aldol reaction
by virtue of the direction of the â-alkoxy group of the methyl
ketone. In the event, formation of the dicyclohexyl boryl
enolate of ketone 3 (Cy2BCl, Et3N, pentane, 0 °C) followed
by addition of aldehyde 4 (-78 °C, 3 h) resulted in a yield
of 82% of the aldol adducts, but in a disappointing 68:32
ratio of 23a:23b (see Table 1).
1
be directly determined by H NMR. Both isomers 22 were
converted to methyl ketone 3 through a three-step oxidation,
methyl Grignard addition, and oxidation sequence. Inspection
of the 1H NMR of ketone 3 indicated a ratio of 15:1 in favor
(17) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.;
MacAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661-5663. Crimmins, M.
T.; Katz, J. D.; Captain, L. F.; Tabet, E. A.; Kirincich, S. J. Org. Lett.
2001, 3, 949-952.
(18) Bhattacharjee, A.; Soltani, O.; De Brabander, J. K. Org. Lett. 2002,
4, 481-484. Diaz, L. C.; Bao, R. Z.; de Sousa, M. A.; Zukeman-Schpector,
J. Org. Lett. 2002, 4, 4325-4327.
(14) Paterson, I.; Yeung, K. S.; Smaill, J. B. Synlett 1993, 774-776.
(15) Abe, N.; Fujisaki, F.; Sumoto, K.; Miyano, S. Chem. Pharm. Bull.
1991, 39, 1167-1170.
(16) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J.
Org. Chem. 1986, 51, 537-540.
Org. Lett., Vol. 5, No. 24, 2003
4643

Scheme 6. Synthesis of Leucascandrolide A Macrolactone 2
Table 1. Aldol Additions of Boron Enolates of Ketone 3
ratio
conditions
P
23a :23b yield, %
Cy2BCl, Et3N, pentane, -78 °C
Cy2BCl, Et3N, pentane, -100 °C
Bu2BOTf, DIEA, Et2O, -78 °C
Cy2BCl, Et3N, pentane, -78 °C
TBS
TBS
TBS
PMB
68:32
68:32
25:75
75:25
96:4
82
88
87
74
81
(-)-DIPCl, Et3N, pentane, -78 °C TBS
Attempts to improve the selectivity by lowering the
reaction temperature and by altering the protecting group of
the â-alkoxy group (TBS to PMB) of the aldehyde met with
no significant change in the diastereoselectivity. Since De
Brabander19 had noted improvements in a similar aldol
addition by changing from the dicyclohexylboryl enolate to
dibutyl or diethylboryl enolate, the dibutylboryl enolate of
3 was tested. Surprisingly, a reversal of the selectivity to
25:75 favoring the 1,5-syn adduct 23b was observed.
Since the dicyclohexylboryl enolate resulted in an aldol
addition favoring the desired 1,5 anti adduct 23a, it seemed
reasonable that the use of the chiral dialkylboron chloride,
(-)-DIPCl,19 might improve the selectivity. Indeed, enoliza-
tion of ketone 3 ((-)-DIPCl, Et3N, pentane, 0 °C), followed
by addition of aldehyde 4 (-78 °C), resulted in a highly
diastereoselective aldol reaction favoring the 1,5 anti adduct
23a (81%, 96:4; 23a:23b).
With all the carbons installed, the â-hydroxy ketone 23a
was readily reduced to the syn-1,3-diol 24 by the action of
diethylmethoxyborane and sodium borohydride.20 2,6-cis-
Disubstituted-tetrahydropyran 25 (12:1 dr) was then obtained
via a hetero-Michael addition when unsaturated ester 24 was
exposed to catalytic t-BuOK in THF. The C9 alcohol was
then converted to methyl ether 26 by treatment with
Meerwein’s salt and 4-methyl-2,6-di-tert-butylpyridine. Both
tert-butyldimethyl silyl groups were removed with TBAF,
and the methyl ester was hydrolyzed with potassium tri-
methylsilanolate to give acid 28.4 Finally, regioselective
macrolactonization under Yamaguchi conditions21 provided
macrocycle 2, which was identical in all respects with
published spectral data and optical rotation.4
The synthesis of the leucascandrolide A macrolactone 2
has been accomplished in a highly convergent 20 linear steps
from propanediol. The synthesis is highlighted by a dia-
stereoselective reductive opening of a bicyclic ketal and a
hetero-Michael addition to construct the two tetrahydropy-
rans, and a (-)-DIPCl-mediated diastereoselective aldol
addition to establish the C7 stereocenter.
Acknowledgment. We thank the National Institutes of
Health (NCI, CA63572) for generous financial support.
Supporting Information Available: Spectral data (1H
and 13C NMR) of macrolactone 2 as well as full experimental
details for the synthesis. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL035797O
(19) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996,
37, 8581-8584.
(20) Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M.
J. Tetrahedron Lett. 1987, 28, 155-158.
(21) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. Hikota, M.; Tone, H.; Horita, K.;
Yonemitsu, O. J. Org. Chem. 1990, 55, 7-9.
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