Enantioselective Preparation of the C1-C11 Fragment of Apoptolidin

Article abstract of DOI:10.1021/ol0361397

(Equation presented) A novel approach toward the synthesis of the triene portion of the biologically active polyketide apoptolidin is described. The use of an iterative thionyl chloride rearrangement/oxidation sequence to construct trisubstituted olefins

Full text of DOI:10.1021/ol0361397

ORGANIC
LETTERS
2004
Vol. 6, No. 1
103-106
Enantioselective Preparation of the
C1−C11 Fragment of Apoptolidin
William D. Paquette and Richard E. Taylor*
Department of Chemistry & Biochemistry and the Walther Cancer
Research Center, UniVersity of Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana 46556-5670
taylor.61@nd.edu
Received November 1, 2003
ABSTRACT
A novel approach toward the synthesis of the triene portion of the biologically active polyketide apoptolidin is described. The use of an
iterative thionyl chloride rearrangement/oxidation sequence to construct trisubstituted olefins is explored.
Apoptolidin, an apoptosis-inducing agent isolated in 1997
from the actinomycete known as Nocardiopsis sp.,1 has been
an inspiring synthetic target in recent years because of its
unique biological activity and structural complexity.2 It was
shown to induce apoptotic activity in E1A-transformed rat
glia cells (IC50 ) 11 ng/mL) while not affecting normal cells.
Recently, Khosla and co-workers proposed a possible
biological mode of action of apoptolidin via the inhibition
of the mitochondrial F0F1-ATPase.3 Apoptolidin consists of
a 20-membered polyunsaturated macrolide appended with a
side chain at C19, which consists of a substituted pyran unit
and two sugar appendages at C9 and C27 (Figure 1).
Our research group is interested in developing a novel
Figure 1.
synthetic route to the apoptolidin aglycone, which would
(1) Kim, J. W.; Adachi, H.; Shin-Ya, K.; Hayakawa, Y.; Seto, H. J.
Antibiot. 1997, 50, 628.
provide us with the opportunity to study its conformational
and biological characteristics. Due to the structural complex-
ity of the aglycone, our synthetic approach involves the
synthesis of three distinct fragments (A-C) with strategic
bond disconnections (Figure 2).
The conjugated (E,E,E)-triene portion of apoptolidin
represented a synthetic target where we could take advantage
of an existing allylic rearrangement method. This thionyl
(2) (a) Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Wei,
H. X.; Weyershausen, B. Angew. Chem., Int. Ed. 2001, 40, 3849. (b)
Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Sugita, K.
Angew. Chem., Int. Ed. 2001, 40, 3854. (c) Nicolaou, K. C.; Li, Y.; Wei,
H. X.; Weyershausen, B. J. Chem. Soc., Chem. Commun. 2000, 307. (d)
Schuppan, J.; Ziemer, B.; Koert, U. Tetrahedron Lett. 2000, 41, 621. (e)
Sulikowski, G. A.; Lee, W. M.; Jin, B.; Wu, B. Org. Lett. 2000, 2, 1439.
(f) Toshima, K.; Arita, T.; Kato, K.; Tanaka, D.; Matsumura, S. Tetrahedron
Lett. 2001, 42, 8873. (g) Schuppan, J.; Wehlan, H.; Keiper, S.; Koert, U.
Angew. Chem., Int. Ed. 2001, 40, 2063. (h) Nicolaou, K. C.; Fylaktakidou,
K. C.; Monenschein, H.; Li, Y.; Weyershausen, B.; Mitchell, H. J.; Wei,
H.; Guntupalli, P.; Hepworth, D.; Sugita, K. J. Am. Chem. Soc. 2003, 125,
15433-15442. (i) Nicolaou, K. C.; Li, Y.; 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, 15443-15454.
(3) (a) Salomon, A. R.; Voehringer, D. W.; Herzenberg, L. A.; Khosla,
C. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 14766. (b) Salomon, A. R.;
Voehringer, D. W.; Herzenberg, L. A.; Khosla, C. Chem. Biol. 2001, 8,
71.
10.1021/ol0361397 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/11/2003

Scheme 2
Figure 2.
chloride allylic rearrangement, pioneered by Young, was
shown experimentally and mechanistically to convert sec-
ondary allylic alcohols into their isomeric primary allylic
chlorides in a stereocontrolled fashion.4 However, to the best
of our knowledge, few have exploited the use of this method
to construct trisubstituted olefins in complex natural product
synthesis.5 Moreover, this method represents a unique
variation, with practical implications, to conventional meth-
ods that include the Wittig, Horner-Wadsworth-Emmons
(HWE) olefinations, and palladium cross-coupling methods.6
Our synthesis toward the triene portion of apoptolidin
began with known aldehyde 1.7 An Evans aldol reaction8
was performed with the aldehyde to generate compound 2
in 83% yield as a white solid following purification (Scheme
1). The diastereomeric ratio was determined to be >20:1 by
ration of the vinyllithium reagent using 2-bromopropene in
the presence of tert-butyllithium followed by aldehyde addi-
tion (Scheme 2). Drying the aldehyde with molecular sieves
prior to addition provided higher yields of the desired alcohol.
The next step in the sequence was to utilize the thionyl
chloride rearrangement methodology to construct the first
trisubstituted olefin. This rearrangement is believed to involve
formation of a chlorosulfinate intermediate, which allows
delivery of the chloride internally (SNi′) or through a tight
ion pair to the allylic carbon.4c
The reaction was performed using 5 equiv of freshly
distilled thionyl chloride (Scheme 2). The potentially acid-
labile TBS ether and vinyl silane moieties are stable under
the thionyl chloride conditions for extended periods of time,
which increases the generality of this reaction. Analysis of
the crude reaction mixtures of these reactions illustrated the
desired primary chloride as the only detectable component
(careful NMR analysis), which was taken onto the next step
without purification.
Scheme 1
The oxidation of the primary chloride to the corresponding
aldehyde can be accomplished with a variety of methods,
including the Kornblum oxidation with modifications10,11 or
the Ganem oxidation.12 In particular, the use of the Kornblum
(4) Some representatative examples: (a) Young, W. G.; Caserio, F.;
Brandon, D. Science 1953, 117, 473. (b) Young, W. G.; Caserio, F.; Dennis,
G. E.; DeWolfe, R. H. J. Am. Chem. Soc. 1955, 77, 4182. (c) Young, W.
G.; Caserio, F.; Brandon, D. J. Am. Chem. Soc. 1960, 82, 6163. (d) Ireland,
R. E.; Wrigley, T. I.; Young, W. G. J. Am. Chem. Soc. 1958, 80, 4604. (e)
Pegolotti, J. A.; Young, W. G. J. Am. Chem. Soc. 1961, 83, 3251.
(5) (a) Johnson, W. S.; Li, T.; Harbert, C. A.; Bartlett, W. R.; Herrin, T.
R.; Staskun, B.; Rich, D. H. J. Am. Chem. Soc. 1970, 92, 4461. (b) Taylor,
R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett. 1998, 39, 9361-
9364. (c) For the use of this method to prepare (Z)-trisubstituted olefins,
see: Taylor, R. E.; Chen, Y. Org. Lett. 2001, 3, 2221. (d) For use of the
thionyl chloride rearrangement within a ring system, see: Trost, B. M.;
Krische, M. J. J. Am. Chem. Soc. 1999, 121, 6131. Trost, B. M.; Haffner,
C.; Krische, M. J. J. Am. Chem. Soc. 1999, 121, 6183.
1
crude H NMR analysis. Protection of the hydroxyl group
with TBSOTf in the presence of 2,6-lutidine afforded
compound 3 in 98% yield. Removal of the chiral auxiliary
with lithium borohydride provided access to alcohol 4 in
90%, which was followed by Dess-Martin periodinane9
oxidation to provide the corresponding aldehyde 5.
(6) For a comparison of iterative HWE and cross-coupling strategies
towards apoptoldin, see ref 2h.
(7) Hwu, J. R.; Furth, P. S. J. Am.. Chem. Soc. 1989, 111, 8834.
(8) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
The synthesis of allylic alcohol 6, obtained in 83% as a
mixture of diastereomers, was accomplished by initial gene-
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
104
Org. Lett., Vol. 6, No. 1, 2004

oxidation in this sequence was not ideal due to the require-
ment of high reaction temperatures (>100 °C). The Ganem
oxidation, which utilizes trimethylamine N-oxide (TMNO)
as the oxidant and is performed at room temperature, is the
preferable method. A modification of the Ganem oxidation
uses N-methylmorpholine-N-oxide (NMO) as the oxidant and
can also be performed under mild conditions.13
Primary chloride 7 was allowed to react with TMNO (5
equiv) in DMSO to afford 8 in 68% over two steps (Scheme
2). The use of NMO as the oxidant was also investigated;
however, the yields were lower.
The conversion of allylic alcohol 11 into the corresponding
primary chloride was performed using thionyl chloride,
which was followed by oxidation with TMNO in DMSO
(as previously illustrated) in an effort to yield the desired
aldehyde. The reaction to form the desired primary chloride
appeared to be clean; however, following the exposure to
oxidant, only trace amounts of aldehyde were observed, per-
haps due to aldehyde instability. Therefore, formation of ace-
tate 12 was accomplished using cesium acetate in DMF at
65 °C to displace the primary chloride. This illustrates that
the thionyl chloride rearrangement is useful for the construc-
tion of (E)-trisubstituted olefins in an iterative fashion.
In addition, the Horner-Wadsworth-Emmons olefination
reaction, along with the Wittig olefination, offers a comple-
mentary approach to triene formation. The advantage of this
reaction is that it provides access to a more stable form of
the triene compared to the aldehyde version in addition to
providing the appropriate oxidation state at C-1. Therefore,
aldehyde 10 was allowed to react with the stabilized anion
generated from triethyl 2-phosphonopropionate and n-BuLi
to provide the desired ester 13 in 90% yield (Scheme 5).
Following the same reaction series as described in Scheme
2, allylic alcohol 9 was prepared as a mixture of diastereo-
mers in 89% (Scheme 3). The allylic alcohol was allowed
Scheme 3
Scheme 5
to undergo the thionyl chloride rearrangement/oxidation
sequence to provide the dienal 10 in 63% over two steps.
The ability to perform the thionyl chloride and oxidation in
a sequence without intermediate purification provides a
useful route in generating aldehydes from their corresponding
allylic alcohols with complete control of olefin geometry,
as determined by careful NMR analysis (E:Z > 20:1).
The installation of the final olefin for the triene was
attempted by the same protocol as previously illustrated.
Aldehyde 10 was allowed to react with the preformed
vinyllithium species to provide allylic alcohol 11 as a mixture
of diastereomers in 80% yield (Scheme 4).
In addition to these efforts, the mild transformation of the
vinyl silane moiety into a vinyl iodide using N-iodosuccin-
imide (NIS) in acetonitrile was also investigated. Kishi
introduced this method in his synthesis toward halichondrin
B where he was able to convert a vinyl silane into its vinyl
iodide in 80% with a 9:1 E/Z ratio.14,15 In his investigation,
Kishi noticed a unique trend where “substrates with bulkier
allylic carbons gave better overall retention of geometry.”
This observation inspired our investigations for utilizing this
reaction in our synthesis. Reaction of aldehyde 10 with NIS
1
resulted in clean conversion by H NMR analysis to vinyl
iodide 14 in 65% yield where the olefin geometry was
exclusively the (E)-isomer (Scheme 6). The other olefins did
not interfere with the reaction.
Scheme 4
Scheme 6
In conclusion, we have demonstrated the iterative use of
thionyl chloride rearrangements to construct conjugated
Org. Lett., Vol. 6, No. 1, 2004
105

trisubstituted olefins with excellent selectivity for the (E)-
configuration. This has been applied toward the synthesis
of the triene portion of apoptolidin. This method serves as a
practical alternative to other known methods for generating
conjugated (E)-olefins. Progress toward the completion of
the aglycone of apoptolidin is currently underway and will
be reported in due course.
thanks Eli Lilly for a Grantee Award. This work was done
in collaboration with the Walther Cancer Research Institute
of Indianapolis, Indiana.
Supporting Information Available: Full experimental
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Jeffrey P. Ciavarri is acknowledged
for preliminary studies. This work was partially supported
by the National Cancer Institute and National Institutes of
Health (CA81128). W.D.P. thanks the University of Notre
Dame for support through a Podrasnik Fellowship. R.E.T.
OL0361397
(13) Griffith, W. P.; Jolliffe, J. M.; Ley, S. V.; Springhorn, K. F.; Tiffin,
P. D. Synth. Commun. 1992, 22, 1967.
(14) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37,
8647.
(15) Other methods: (a) Barluenga, J.; Alvarez-Garcia, L. J.; Gonzalez,
J. M. Tetrahedron Lett. 1995, 36, 2153. (b) Chan, T. H.; Koumaglo, K.
Tetrahedron Lett. 1986, 27, 883. (c) Alimardanov, A.; Negishi, E.
Tetrahedron Lett. 1999, 40, 3839. (d) Miller, R. B.; Reichenbach, T.
Tetrahedron Lett. 1974, 6, 543.
(10) (a) Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc.
1959, 81, 4113. (b) Kornblum, N.; Jones, W. J.; Anderson, G. J.; Powers,
J. W.; Larson, H. O.; Levand, O.; Wraver, W. M. J. Am. Chem. Soc. 1957,
79, 6562.
(11) Dave, P.; Byun, H. S.; Engel, R. Synth. Commun. 1986, 16, 1343.
(12) Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1990, 31, 4825.
106
Org. Lett., Vol. 6, No. 1, 2004