Total synthesis of apoptolidin A

Article abstract of DOI:10.1021/ol802829n

A highly convergent, enantioselective total synthesis of the potent antitumor agent apoptolidin A has been completed. The key transformations include highly selective glycosylations to attach the C27 disaccharide and the C9 6'-deoxy-L-glucose, a cross-met

Full text of DOI:10.1021/ol802829n

ORGANIC
LETTERS
2009
Vol. 11, No. 4
831-834
Total Synthesis of Apoptolidin A
Michael T. Crimmins,* Hamish S. Christie, Alan Long, and Kleem Chaudhary
Venable and Kenan Laboratories of Chemistry, Department of Chemistry, UniVersity of
North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received December 8, 2008
ABSTRACT
A highly convergent, enantioselective total synthesis of the potent antitumor agent apoptolidin A has been completed. The key transformations
include highly selective glycosylations to attach the C27 disaccharide and the C9 6′-deoxy-L-glucose, a cross-metathesis to incorporate the
C1-C10 trienoate unit, and a Yamaguchi macrolactonization to complete the macrocycle. Twelve stereocenters in the polypropionate segments
and sugar units were established through diastereoselective chlorotitanium enolate aldol reactions.
Apoptolidins A-D (Figure 1) are secondary metabolites of
Nocardiopsis sp. which are potent, selective inducers of
programmed cell death in rat glia cells transformed with the
adenovirus E1A oncogene. Apoptolidin A was isolated by
Hayakawa in 1997, and its structure was elucidated by a
combination of NMR spectroscopy and molecular modeling
techniques.1 The minor metabolites apoptolidins B, C, and
D were recently isolated and identified by Wender.2,3
Importantly, apoptolidin A has no effect on normal cells at
concentrations as high as 88 µM, while the E1A transformed
glial cells undergo apoptotic cell death when exposed to
apoptolidin A at concentrations of 10 nM.1 This selective
activity of cancer therapeutics is a major factor in minimizing
side effects of chemotherapeutic agents.
The apoptolidins have been the subject of intense synthetic
and biological4 investigations because of their potential as
agents for the treatment of cancer.5 Two total syntheses of
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Figure 1. Structure of the apoptolidins.
10.1021/ol802829n CCC: $40.75
Published on Web 01/22/2009
2009 American Chemical Society

apoptolidin A,6 several syntheses of the aglycon, known as
could be adapted to a synthesis of apoptolidin A by a late-
stage attachment of the sugar units to advanced intermediates
in the apoptolidinone synthesis.
apoptolidinone,7 including one from our laboratory,8
a
number of partial syntheses,9 as well as selective synthetic
modifications10 have been reported.
The glycosyl fluoride 4 derived from L-olivomycose and
D-oleandrose would be utilized to attach the required
disaccharide at C27 of mixed ketal 2 or a similar advanced
intermediate prior to incorporation of the trienoate 3.
Sulfoxide 5 would serve as the glycosylating agent for the
incorporation of the 6′-deoxy-L-glucose unit at C9 either
immediately before or after assembly of the C1-C10 and
C11-C28 subunits via a stereoselective olefin cross-metath-
esis reaction. Mixed ketal 2 and trienoate 3 were advanced
intermediates in our recently reported synthesis of apopto-
lidinone.8
Scheme 1. Retrosynthesis for Apoptolidin A
The required glycosyl donors 4 and 5 for the incorporation
of the sugar units were obtained as illustrated in Schemes 2
and 3. Each of the individual monosaccharide units were
obtained by de novo synthesis through the application of a
chlorotitanium glycolate aldol approach to establish the C4
and C5 stereocenters of each of the monosaccharides.9e
Scheme 2. Synthesis of the C27 Disaccharide
The necessary glycosyl fluoride 4 was accessed from the
protected disaccharide 10 as shown in Scheme 2. Direct
exposure of the hemiacetal 10 to DAST provided the glycosyl
fluoride 4 (>10:1 R:ꢀ).6c Since the glycosyl fluoride was
somewhat unstable, it was utilized in the subsequent glyco-
sylation of the C27 hydroxyl group without further purifica-
tion.
The synthesis of 6′-deoxy-L-glucose (the C9 sugar unit)
donor 5 was readily accomplished from lactone 69e (Scheme
3). Protection of the diol as the corresponding TBS ether 7
was followed by reduction of the lactone with i-Bu2AlH to
deliver the protected 6′-deoxy-L-glucose 8. The hemiacetal
Apoptolidin A (1, Scheme 1) is comprised of a macro-
cyclic lactone and two unusual carbohydrate units attached
through glycosidic linkages at the C9 and C27 hydroxyl
groups. Our highly convergent approach to the synthesis of
apoptolidin A focused initially on the individual preparation
of the aglycon, apoptolidinone,8 and the carbohydrate units,9e
with the expectation that the approach to apoptolidinone
(6) (a) Wehlan, H.; Dauber, M.; Fernaud, M. T. M.; Schuppan, J.;
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B.; Wei, H. X. J. Chem. Soc., Chem. Commun. 2000, 307. (i) Paquette,
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832
Org. Lett., Vol. 11, No. 4, 2009

Attachment of the C27 disaccharide could be accomplished
in high yield (74%) with excellent stereoselectivity (7:1, R:ꢀ)
by treatment of C27 alcohol 2 with stannous chloride in the
presence of glycosyl fluoride 4. The C13 acetate was
selectively cleaved in the presence of the C19,20 carbonate
whereupon the resulting primary alcohol was oxidized under
Swern11 conditions to produce aldehyde 11 in 89% yield.
Two sequential Wittig olefinations completed the synthesis
of diene 12 in 80% overall yield. Alternately, the diene unit
could be incorporated prior to the attachment of the C27
discaccharide. The C27 alcohol 2 was protected as its
triethylsilyl ether followed by removal of the C13 acetate
and subsequent oxidation of the alcohol to the aldehyde 13.
Stabilized Wittig olefination of the aldehyde in chlorobenzene
at 90 °C was accompanied by cleavage of the C27 TES ether.
Methylenation of the unsaturated aldehyde provided the
desired diene alcohol 14. Stereoselective glycosylation of
the C27 alcohol 14 as described previously for alcohol 2
delivered diene 12 in excellent yield.
Scheme 3. Synthesis of the C9 Sugar Unit
8 was converted to mixed acetal 9 ((5:1 R:ꢀ) by exposure to
PhSSiMe3 in the presence of ZnI2. The required glycosyl
donor 5 was obtained as a 2.5:1 mixture of isomers in 72%
yield by oxidation of the thioacetal with m-CPBA.6c
The asssembly of the four key subunits for the completion
of the synthesis of apoptolidin A began with the modification
of mixed ketal 2. Mixed ketal 2 was an advanced intermedi-
ate from the recently completed synthesis of apoptolidinone,
and was available in multigram quantities through 17
synthetic steps involving an interative aldol sequence.8
The key C11-C28 diene 12 was accessible by either of
two sequences from hemiketal 2 as illustrated in Scheme 4.
Completion of the synthesis of apoptolidin A is illustrated
in Scheme 5. Exposure of the alkenes 38 and 12 to the Grubbs
heterocyclic carbene catalyst [Cl2(Cy3P)(IMes)RudCHPh]12
provided the desired E isomer 15 through a critical complex
cross-metathesis8,13 in good yield (>95:5 E:Z by H NMR
1
analysis). An attempted cross-metathesis reaction failed when
the reaction was performed after the glycosidation of the C9
oxygen. To complete the synthesis of apoptolidin A, attach-
ment of the sugar unit at C9 and macrolactonization were
Scheme 4. Attachment of the C27 Disaccharide
Org. Lett., Vol. 11, No. 4, 2009
833

Scheme 5. Synthesis of Apoptolidin A
required. A mixture of alcohol 15 and sulfoxide 5 was
exposed to triflic anhydride stereoselectively providing the
glycoside 16. Treatment of the ester 16 with LiOH at room
temperature rapidly cleaved the carbonate group and eventu-
ally the ester, to give a good yield of the desired seco acid.
Regioselective macrolactonization at C19 proceeded smoothly
under Yamaguchi’s conditions to deliver the macrolactone.14
Finally, cleavage of the silyl ethers and hydrolysis of the
mixed methyl acetal were effected in one operation with
H2SiF6 to furnish apoptolidin A (1). Synthetic apoptolidin
A was identical with an authentic sample.
The successful total synthesis utilized diastereoselective
chlorotitanium aldol reactions to establish 12 (carbons 4′,5′;
4′′,5′′; 4′′′,5′′′; 8,9; 22,23; and 24,25) of the 24 stereocenters
of apoptolidin A and exploited a complex cross-metathesis
to assemble the two major fragments and construct the
C10-C13 diene unit.
Acknowledgment. Financial support from the National
Cancer Institute (CA63572) is gratefully acknowledged. We
thank Professor Paul A. Wender and Dr. Kate Longcore,
Stanford University, for generously supplying an authentic
sample of apoptolidin A.
(11) Swern, D.; Mancuso, A. J.; Huang, S. J. Org. Chem. 1978, 43,
2480.
Supporting Information Available: Experimental pro-
cedures and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(13) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(14) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
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