Published on Web 11/21/2003
Total Synthesis of Apoptolidin: Completion of the Synthesis
and Analogue Synthesis and Evaluation
K. C. Nicolaou,*,† Yiwei Li,† Kazuyuki Sugita,† Holger Monenschein,†
Prasuna Guntupalli,† Helen J. Mitchell,† Konstantina C. Fylaktakidou,†
Dionisios Vourloumis,† Paraskevi Giannakakou,‡ and Aurora O’Brate‡
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093, and Winship Cancer Institute,
Emory UniVersity School of Medicine, Atlanta, Georgia 30322
Received August 18, 2003; E-mail: kcn@scripps.edu
Abstract: The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological
evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane
coupling technology was supplemented by a second generation route to this advanced intermediate involving
a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured
a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of
glycosidations, and final deprotection. The developed synthetic technology was applied to the construction
of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.
Introduction
toward apoptolidin (1) called for the coupling of aldehyde 6
In the preceding paper1 we discussed a retrosynthetic blueprint
for apoptolidin (1) and described studies that led to the
construction of the proposed building blocks required for the
total synthesis of this formidable synthetic target. In this article,
we detail our investigations which culminated in the first total
synthesis of 1 and several of its analogues.
(C12-C20 fragment) with dithiane 7 (C21-C28 fragment) and
elaboration to vinyl iodide 3. Scheme 1 summarizes the initial
stages of this directive, whereas Scheme 2 depicts the comple-
tion of the task. Thus, lithiation of dithiane 7 with tert-
butyllithium in the presence of HMPA in THF at -78 °C
followed by cooling to -100 °C and addition of aldehyde 6
resulted in the generation of coupling product 8a,b (mixture of
Results and Discussion
C20 epimers, ca. 1.5:1 ratio). Attempts aimed at improving the
Figure 1 depicts a brief version of the retrosynthetic blueprint
for apoptolidin (1), whose more detailed analysis was presented
in the preceding paper. According to this analysis, the projected
strategy calls for the assembly of fragments 2 and 4-7 to the
final target via a sequence involving, in order of construction,
the following key steps: (a) a dithiane coupling between 6 and
7 and elaboration of the resulting intermediate to a suitable vinyl
iodide partner (3); (b) a Stille coupling to join vinyl iodide 3
with vinylstannane 2; (c) glycosidation of the formed intermedi-
ate and advancement to a seco acid; (d) Yamaguchi macrolac-
tonization and elaboration to a more advanced intermediate; (e)
glycosidation to attach the final disaccharide domain; and (f)
final deprotection. We will begin the discussion of the total
synthesis of apoptolidin (1) with our first attempt to construct
the challenging vinyl iodide 3.
diastereoselectivity of this reaction by changing the conditions
(e.g., additives, base)2 failed, but since we did not know at this
stage the stereochemistry of the two isomers, we opted to press
on until assignment could be made. Thus, each of the chro-
matographically separated isomers 8a and 8b was taken through
the sequence as follows. First, the TBS groups were removed
from the C16, C23, and C25 hydroxyl groups with TBAF (90%
yield), forming 9a and 9b, compounds from which the dithiane
3
moiety was cleaved through the action of PhI(OCOCF3)2 to
afford 10a and 10b (collapse of C25 hydroxy group onto the
newly unveiled carbonyl group at C21). Tetraols 10a and 10b
were then converted to their bis-silylated counterparts 11a and
11b by careful exposure to 2.5 equiv of TBSOTf in dichlo-
romethane in the presence of 2,6-lutidine at -78 °C (78% yield,
two steps). At this stage, an opportunity arose to rigidify the
molecules around their C20-C21 regions for NMR spectroscopic
analysis through preparation of cyclic carbonate derivatives. To
this end, 11a and 11b were exposed to the action of triphosgene
1. Coupling of Building Blocks 6 and 7 and Synthesis of
Vinyl Iodide 3. Beyond the construction of the key building
blocks described in the preceding paper, the designed strategy
(2) For examples of stereochemically controlled dithiane coupling reactions,
see: (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi,
H.-S. J. Am. Chem. Soc. 2002, 124, 2190-2201. (b) Smith, A. B., III;
Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka,
R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947-961.
† The Scripps Research Institute and University of California, San Diego.
‡ Winship Cancer Institute.
(1) Nicolaou, K. C.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y.; Weyer-
shausen, B.; Mitchell, H. J.; Wei, H.; Guntupalli, P.; Hepworth, D.; Sugita,
K. J. Am. Chem. Soc. 2003, 125, 15433-15442.
(3) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
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10.1021/ja030496v CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 15443-15454
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