Enantioselective synthesis of apoptolidin sugars

Article abstract of DOI:10.1021/ol0515107

(Chemical Equation Presented) The de novo synthesis of the C9 and C27 sugar subunits (2) and (3), respectively, of the potent antitumor agent, apoptolidin, has been accomplished. A titanium tetrachloride-mediated asymmetric anti glycolate aldol addition w

Full text of DOI:10.1021/ol0515107

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4157-4160
Enantioselective Synthesis of
Apoptolidin Sugars
Michael T. Crimmins* and Alan Long
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 June 28, 2005
ABSTRACT
The de novo synthesis of the C9 and C27 sugar subunits (2) and (3), respectively, of the potent antitumor agent, apoptolidin, has been
accomplished. A titanium tetrachloride-mediated asymmetric anti glycolate aldol addition was utilized to establish the 4 and 5 stereogenic
-selective
′
′
centers of each of the three monosaccharides. Elaboration of the aldol adducts efficiently provided the three sugar units. A
glycosidation completed the construction of the C27 disaccharide.
â
Apoptolidins A-C are potent, selective mediators of pro-
grammed cell death in rat glia cells transformed with the
adenovirus E1A oncogene. Since its isolation and structure
elucidation by Hayakawa in 1997,1 apoptolidin A (1) has
been the subject of intense synthetic and biological2 inves-
tigations because of its potential as a therapeutic agent for
the treatment of cancer. Two total syntheses,3 a number of
partial syntheses,4 as well as selective synthetic modifica-
tions5 have been reported. The minor metabolites apoptolidins
B and C were recently isolated and identified by Wender.6
has focused on the individual preparation of the aglycone,
apoptolidinone, and the carbohydrate units, with the intent
of a late-stage attachment of the sugars to an advanced
intermediate in the apoptolidinone synthesis. The successful
Apoptolidin A (1, Figure 1) is comprised of a macrocyclic
aglycone, known as apoptolidinone, and two carbohydrate
units attached through glycoside linkages at the C9 and C27
hydroxyl groups. Our approach to the synthesis of apoptolidin
(1) (a) Kim, J. W.; Adachi, H.; Shin-ya, K.; Hayakawa, Y.; Seto, H. J.
Antibiot. 1997, 50, 628. (b) Hayakawa, Y.; Kim, J. W.; Adachi, H.; Shin-
ya, K.; Fujita, K.; Seto, H. J. Am. Chem. Soc. 1998, 120, 3524.
(2) (a) Salomon, A. R.; Voehringer, D. W.; Herzenberg, L. A.; Khosla,
C. Chem. Biol. 2001, 8, 71. (b) Salomon, A. R.; Zhang, Y. B.; Seto H.;
Khosla, C. Org. Lett. 2001, 3, 57. (c) Salomon, A. R.; Voehringer, D. W.;
Herzenberg, L. A.; Khosla, C. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 14766.
Figure 1. Structure of the apoptolidins.
10.1021/ol0515107 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/25/2005

preparation of the three monosaccharides and a stereoselec-
tive glycosidation to construct the C27 disaccharide are the
subject of this report.
Scheme 1. Synthesis of the C9 Sugar Unit
Each of the three sugar units of apoptolidin is a 6′-deoxy
sugar. Interestingly, the C9 monosaccharide is a 6′-deoxy-
L-sugar (6′-deoxy-L-glucose), while the disaccharide at C27
is derived from one 6′-deoxy-L-sugar (L-olivomycose) and
one 6′-deoxy-D-sugar (D-oleandrose). One rational approach
to the preparation of the three deoxy sugar units and the
approach taken by both the Nicolaou and Koert groups3
would be to synthetically modify natural carbohydrates to
obtain the desired fragments. In contrast, we chose to carry
out a de novo synthesis of the three monosaccharides since
an asymmetric anti glycolate aldol addition could be
exploited to establish the C4 and C5 stereocenters of each
of the monosaccharides.
The synthesis of 6′-deoxy-L-glucose (the C9 sugar unit)
derivative 11 is illustrated in Scheme 1. The chlorotitanium
enolate of O-methyl glycolyloxazolidinethione 4 was treated
with acetaldehyde in the presence of excess TiCl4 at -78
°C to provide aldol adduct 5 as a 15:1 mixture of diastere-
omers.7 A single recrystallization of the product provided
the major anti diastereomer in 80% isolated yield. The critical
aldol reaction served to establish the C4 and C5 stereocenters
and confirm the viability of our plan for each of the three
(3) (a) Wehlan, H.; Dauber, M.; Fernaud, M. T. M.; Schuppan, J.;
Mahrwald, R.; Ziemer, B.; Garcia, M. E. J.; Koert, U. Angew. Chem., Int.
Ed. 2004, 43, 4597. (b) Nicolaou, K. C.; Fylaktakidou, K. C.; Monenschein,
H.; Li, Y. W.; Weyershausen, B.; Mitchell, H. J.; Wei, H. X.; Guntupalli,
P.; Hepworth, D.; Sugita, K. J. Am. Chem. Soc. 2003, 125, 15433. (c)
Nicolaou, K. C.; Li, Y. W.; Sugita, K.; Monenschein, H.; Guntupalli, P.;
Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2003, 125, 15443. (d) Nicolaou, K. C.; Li,
Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Sugita, K. Angew. Chem., Int. Ed.
2001, 40, 3854. (e) Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell,
H. J.; Wei, H. X.; Weyershausen, B. Angew. Chem., Int. Ed. 2001, 40,
3849.
(4) (a) Crimmins, M. T.; Long, A. Abstr. Papers Am. Chem. Soc. 2004,
228: U35-U35 103-ORGN. (b) Jin, B. H.; Liu, Q. S.; Sulikowski, G. A.
Tetrahedron 2005, 61, 401. (c) Wu, B.; Liu, Q. S.; Sulikowski, G. A. Angew.
Chem., Int. Ed. 2005, 43, 6673. (d) Abe, K.; Kato, K.; Arai, T.; Rahim, M.
A.; Sultana, I.; Matsumura, S.; Toshima, K. Tetrahedron Lett. 2004 45,
8849. (e) Paquette, W. D.; Taylor, R. E. Abstr. Papers Am. Chem. Soc.
2003, 225: U319-U320 241-ORGN. (f) Wu, B.; Jin, B. H.; Qu, T.; Liu,
Q. S.; Sulikowski, G. A. Abstr. Papers Am. Chem. Soc. 2003, 225: U321-
U321 247-ORGN. (g) Ross, N. A.; Taylor, R. E.; Paquette, W. D.; Guseilla,
D. J. Abstr. Papers Am. Chem. Soc. 2003, 226: U228-U229 677-ORGN.
(h) Li, X. J.; Fuchs, P. L. Abstr. Papers Am. Chem. Soc. 2003, 226: U229-
U229 680-ORGN. (i) Paquette, W. D.; Taylor, R. E. Org. Lett. 2004, 6,
103. (j) Chang, S. S.; Xu, J.; Loh, T. P. Tetrahedron Lett. 2003, 44, 4997.
(k) Pennington, J. D.; Williams, H. J.; Salomon, A. R.; Sulikowski, G. A.
Org. Lett. 2002, 4, 3823. (l) Chen, Y. Z.; Evarts, J. B.; Torres, E.; Fuchs,
P. L. Org. Lett. 2002, 4, 3571. (m) Chen, Y. Z.; Fuchs, P. L. Abstr. Papers
Am. Chem. Soc. 224: 640-ORGN, Part 2, Aug. 18, 2002. (n) Whiteker, L.
B. Abstr. Papers Am. Chem. Soc. 2002, 223: 840-CHED. (o) Schuppan,
J.; Wehlan, H.; Keiper, S.; Koert, U. Angew. Chem., Int. Ed. 2001, 40,
2063. (p) Toshima, K.; Arita, T.; Kato, K.; Tanaka, D.; Matsumura, S.
Tetrahedron Lett. 2001, 42, 8873. (q) Schuppan, J.; Ziemer, B.; Koert, U.
Tetrahedron Lett. 2000, 41, 621. (r) Sulikowski, G. A.; Jin, B. H.; Lee, W.
M.; Wu, B. Org. Lett. 2000, 2, 1439. (s) Chen, Y. Z.; Fuchs, P. L. Abstr.
Papers Am. Chem. Soc. 2002, 224, U246. (t) Chaudhary, K.; Crimmins,
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816-ORGN.
sugar units. Alcohol 5 was protected as its triethylsilyl ether
with triethylsilyl triflate and 2,6-lutidine; subsequent reduc-
tive removal of the imide provided the primary alcohol 6 in
94% yield. Oxidation of the primary alcohol to the aldehyde
was immediately followed by a Horner-Wadsworth-
Emmons olefination to deliver the required enoate 7 in 89%
yield over two steps. A Sharpless asymmetric dihydroxyla-
tion8 was exploited to incorporate the remaining C2 and C3
stereocenters. Employing AD-mix-â to execute the dihy-
droxylation provided a 7:1 mixture of syn diols in 79%
overall yield with diol 8 as the major product. Dihydroxy-
lation without the use of a chiral ligand resulted in the
formation of diol 8 as the minor product. Fluoride-mediated
removal of the triethylsilyl group led to spontaneous cy-
clization to the lactone 9. The diol 9 was converted to the
silyl ether 10 with triethylsilyl triflate and 2,6-lutidine in 98%
yield. Finally, reduction of the lactone 10 with i-Bu2AlH
provided hemiacetal 11 as a 5:1 mixture of anomers.
The synthesis of both sugar units required for the C27
disaccharide also began with an anti selective glycolate aldol
reaction. Scheme 2 illustrates the preparation of the required
D-oleandrose derivative 18. Enolization of the N-acyloxazo-
lidinethione 13 with TiCl4 and (-)-sparteine with ensuing
addition of 2 further equiv of TiCl4 and acetaldehyde gave
the aldol adduct 14 in 90% yield (13:1 dr). Direct displace-
ment of the oxazolidinethione by N-methyl-O-methylhy-
droxylamine in the presence of imidazole produced the
Weinreb amide. Protection of the hydroxyl group and
(5) (a) Wender, P. A.; Jankowski, O. D.; Tabet, E. A.; Seto, H. Org.
Lett. 2003, 5, 2299. (b) Wender, P. A.; Jankowski, O. D.; Tabet, E. A.;
Seto, H. Org. Lett. 2003, 5, 487. (c) Wender, P. A.; Gulledge, A. V.;
Jankowski, O. D.; Seto, H. Org. Lett. 2002, 4, 3819.
(6) Wender, P. A.; Sukopp, M.; Longcore, K. Org. Lett. 2005, 7, 3025.
(7) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591.
(8) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483. (b) Kolb, H. C.; Andersson, P. G.; Bennani, Y. L.; Crispino,
G. A.; Jeong, K.-S.; Kwong, H.-L.; Sharpless, K. B. J. Am. Chem. Soc.
1993, 115, 12226.
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Org. Lett., Vol. 7, No. 19, 2005

Scheme 2. Synthesis of the C27 Sugar Unit
Scheme 3. Synthesis of the C27 Sugar Unit
p-TsOH. The desired hemiacetal 24 was obtained by sily-
lation of the C4 hydroxyl and hydrogenolysis of the mixed
benzyl acetal.
subsequent conversion of the Weinreb amide to the methyl
ketone 15 proceeded smoothly (79%, three steps). The
tertiary carbinol center was established with >20:1 diaste-
reoselectivity (99% yield) by a chelation-controlled allylation
utilizing MgBr2-OEt2 and allyltributylstannane.9 The alcohol
16 was converted to silyl ether 17 by removal of the allyl
ether according to conditions described by Cha,10 followed
by selective protection of the secondary alcohol as its
triethylsilyl ether. Standard oxidative cleavage of the terminal
alkene, formation of the mixed benzyl acetal, and cleavage
of the silyl ether delivered acetal 18 in good overall yield.
The third and final sugar unit (an L-olivomycose deriva-
tive) was prepared as illustrated in Scheme 3. The synthesis
began with ent-14, the aldol adduct produced from the
addition of the enantiomer of N-acyloxazolidinethione 13 to
acetaldehyde (Scheme 2). Protection of the secondary
hydroxyl, reductive removal of the oxazolidinethione, and
oxidation of the primary alcohol under Swern11 conditions
produced aldehyde 19 in 89% overall yield. Once again, a
chelation-controlled addition effected by MgBr2‚OEt2 and
allyltributylstannane was exploited, in this instance, to
establish the C3 secondary carbinol stereocenter of alcohol
20. The alcohol was methylated with Me3OBF4, and the allyl
ether was cleaved with Ti(O-i-Pr)4-n-BuMgCl9 to give
alcohol 21. Oxidative cleavage of the terminal alkene
produced the five-membered ring hemiacetal 22, which was
readily converted under thermodynamic control to the six-
membered ring acetal 23 by exposure to benzyl alcohol and
The completion of the C27 disaccharide unit required a
stereoselective glycosidation reaction employing hemiacetal
24 as the glycosyl donor and sugar 18 as the glycosyl
acceptor. Two challenges are immediately apparent for the
selective coupling of these two monosaccharides. The first
is that the glycosyl donor 24 is devoid of any steric or
anchimeric directing functionality at the 2′ position, a typical
requirement for the selective construction of a â-glycoside
linkage. Second, there is a question of regioselectivity with
sugar 18 since it has both secondary and tertiary free
hydroxyl groups. These challenges were successfully met
by using a glycosidation reported by Binkley.12 The glycosyl
bromide 25 was generated in situ by exposure of hemiacetal
24 to Me3SiBr in benzene. Immediate treatment of the
Scheme 4. Synthesis of the C27 Disaccharide
(9) Charette, A. B.; Benslimane, A. F.; Mellon, C. Tetrahedron Lett.
1995, 36, 8557.
(10) Lee, J.; Cha, J. K. Tetrahedron Lett. 1996, 37, 3663.
(11) Swern, D.; Mancuso, A. J.; Huang, S. J. Org. Chem. 1978, 43, 2480.
Org. Lett., Vol. 7, No. 19, 2005
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glycosyl bromide with Ag2O-silica gel in the presence of
diol 18 produced the desired glycoside as a 6:1 mixture of
anomers with the â-anomer as the major isomer (68%). Only
trace amounts of disaccharide were formed as a result of
the coupling via the tertiary hydroxyl of diol 18. The
configuration of the disaccharide coupling was established
using two-dimensional NMR spectroscopy. The coupling
product 26 was converted into the known3b,c intermediate
27 by protection of the tertiary hydroxyl group in 91% yield
using triethylsilyl triflate and 2,6-lutidine in CH2Cl2 and final
hydrogenolysis of the benzyl acetal with 10% Pd/C in ethanol
(78% overall yield). Hemiacetal 27 was spectroscopically
identical to the key intermediate advanced by Nicolaou in
the first total synthesis of apoptolidin.3b,c
The three monosaccharide subunits of the potent antitumor
agent, apoptolidin, have been synthesized using an asym-
metric anti glycolate aldol as the critical step in the synthesis
of each sugar. A selective â-glycosidation to prepare the C27
disaccharide has also been accomplished without the aid of
a 2′ directing group. Synthesis of apoptolidinone and further
studies on the total synthesis of apoptolidin utilizing the sugar
subunits reported herein are in progress and will be reported
in due course.
Acknowledgment. Financial support from the National
Cancer Institute (CA63572) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures and copies of H NMR spectra. This material is
(12) Binkley, R. W.; Koholic, D. J. J. Org. Chem. 1989, 54, 3577. See
also: Kihlberg, J.; Holm, B.; Broddefalk, J.; Flodell, S.; Wellner, E.
Tetrahedron 2000, 56, 1579.
available free of charge via the Internet at http://pubs.acs.org.
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