A R T I C L E S
Nicolaou et al.
easily modified to accommodate the chemical sensitivity and
complexity of the molecule; (2) a convergent route that would
allow convenient access to designed analogues in order to probe
structure-activity relationships. The chemical sensitivity of this
target molecule is primarily a reflection of the labile nature of
its macrocyclic ring with its all-trans polyene systems, the
susceptibility of the disaccharide domain toward acid hydrolysis,
and the migratory tendencies of the acyl chain of the macro-
lactone from C19 to the other hydroxyl groups under basic
conditions.9 In light of these potentially problematic issues, we
had to exercise special prudence in drafting a suitable road map
toward the target molecule (1) that would avoid both acidic and
basic media in the final stages. We also had to rely on silicon
protecting groups which could, in principle, be removed under
mild and neutral conditions at the end of the campaign.10
Figure 1. Molecular structure of apoptolidin (1).
its macrocyclic system and the 6-deoxy-glucose residue.6 As
shown in Figure 1, the structure of apoptolidin (1) contains a
20-membered macrolide ring equipped with a side chain
carrying a six-membered hemiketal system. The molecule also
carries a disaccharide moiety made of a D-oleandrose unit and
an L-olivomycose ring, as well as a novel 6-deoxy-glucose
residue. The molecular architecture of apoptolidin is distin-
guished by a total of 25 stereocenters and 5 geometrical sites
and features several unsaturated sites within its macrocyclic
scaffold, a densely substituted hemiketal ring, and two 2-deoxy-
pyranoses. The promising biological activity and daunting
molecular architecture of apoptolidin (1) have stimulated a
considerable body of synthetic work directed toward its total
synthesis. Thus, besides our own, investigations have been
reported by the Koert, Sulikowski, Toshima, Fuchs, and Loh
groups, among others.7 In addition, the Wender group has
engaged in semisynthetic studies directed toward the preparation
of analogues for biological screening purposes.8
The synthetic challenge posed by the apoptolidin structure
offers a unique opportunity for discovery and invention in the
area of new synthetic strategies and technologies. Furthermore,
such an endeavor, if successful, may provide validation to
apoptolidin’s structure and open entries into analogues for
biological investigations, leading to useful structure-activity
relationships (SAR). In this and the following article, we
describe a full account of our synthetic investigations in this
area, which culminated in the first total synthesis of apoptolidin
(1) and biological evaluation of a series of relevant analogues.
1. Retrosynthetic Analysis. The overall retrosynthetic analy-
sis of the target molecule, apoptolidin (1), is shown in Figure
2. Thus, given the high sensitivity of the DE disaccharide unit,
this domain was excised first, leading, upon appropriate
protecting group installment, to advanced intermediate 2 as a
potential precursor. Note that 2 is suitably protected to serve as
a substrate for glycosidation with glycosyl donor 4, in the
synthetic direction, a process that can also be applied to the
construction of analogues with varying sugar residues at C27.
The stereochemistry of the glycoside bond linking this disac-
charide group (DE) to the mainframe of the molecule is R and,
thereby, should pose no particular challenge as it is the one
anomerically favored.
While disaccharide 4 can easily be traced to readily available
carbohydrate units (10 and 11), the macrolide portion 2 still
needs considerable trimming before readily accessible fragments
can be recognized. From all possible (and there are many)
retrosynthetic disconnections for the rupture of the macrocycle,
we chose the Yamaguchi lactone-forming reaction11 for its
reliability and proven record in highly complex settings, a
scission that together with the indicated retro-glycosidation led
to trihydroxy acid 3 and carbohydrate unit 5. The sulfoxide
glycosyl donor 5 was chosen in order to ensure the desired
R-glycoside bond formation at low temperature and under mild
conditions as expected from a Kahne protocol.12 With regards
to seco acid 3, it was anticipated that the conformational rigidity
and constrain conferred to the backbone by its olefinic bonds,
Results and Discussion
(9) During the course of this synthetic endeavor, Khosla reported the stability
problem with apoptolidin. We subsequently reported, in our total synthesis
communications, the labile nature of apoptolidin and its tendency toward
isomerization. Wender and Sulikowski later isolated and identified the major
isomer as isoapoptolidin. For detailed information, see: (a) Salomon, A.
R.; Voehringer, D. W.; Herzenberg, L. A.; Khosla, C. Chem. Biol. 2001,
8, 71-80. (b) Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H.
J.; Sugita, K. Angew. Chem., Int. Ed. 2001, 40, 3854-3857. (c) Wender,
P. A.; Gulledge, A. V.; Jankowski, O. D.; Seto, H. Org. Lett. 2002, 4,
3819-3822. (d) Pennington, J. D.; Williams, H. J.; Salomon, A. R.;
Sulikowski, G. A. Org. Lett. 2002, 4, 3823-3825. For information on its
sensitivity toward acidic conditions, see also: (e) Salomon, A. R.; Zhang,
Y.; Seto, H.; Khosla, C. Org. Lett. 2001, 3, 57-59. (b) Hayakawa, Y.;
Kim, J. W.; Adachi, H.; Shin-ya, K.; Fujita, K.; Seto, H. J. Am. Chem.
Soc. 1998, 120, 3524-3525.
In contemplating a synthetic strategy for the total synthesis
of apoptolidin (1), we kept in mind the following objectives:
(1) a stereocontrolled, yet flexible approach which could be
(6) Hayakawa, Y.; Kim, J. W.; Adachi, H.; Shin-ya, K.; Fujita, K.; Seto, H. J.
Am. Chem. Soc. 1998, 120, 3524-3525.
(7) (a) Schuppan, J.; Ziemer, B.; Koert, U. Tetrahedron Lett. 2000, 41, 621-
624. (b) Nicolaou, K. C.; Li, Y.; Weyershausen, B.; Wei, H.-X. Chem.
Commun. 2000, 4, 307-308. (c) Sulikowski, G. A.; Lee, W.-M.; Jin, B.;
Wu, B. Org. Lett. 2000, 2, 1439-1442. (d) Schuppan, J.; Wehlan, H.;
Keiper, S.; Koert, U. Angew. Chem., Int. Ed. 2001, 40, 2063-2066. (e)
Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Wei, H.-X.;
Weyershausen, B. Angew. Chem., Int. Ed. 2001, 40, 3849-3854. (f)
Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Sugita, K.
Angew. Chem., Int. Ed. 2001, 40, 3854-3857. (g) Toshima, K.; Arita, T.;
Kato, K.; Tanaka, D.; Matsumura, S. Tetrahedron Lett. 2001, 42, 8873-
8876. (h) Chen, Y.; Evarts, J. B., Jr.; Torres, E.; Fuchs, P. L. Org. Lett.
2002, 4, 3571-3574. (i) Chng, S.-S.; Xu, J.; Loh, T.-P. Tetrahedron Lett.
2003, 44, 4997-5000.
(10) For an excellent review on selective deprotection of silyl ethers, see: Nelson,
T. D.; Crouch, R. D. Synthesis 1996, 1031-1069.
(11) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993. (b) Hikota, M.; Tone, H.; Horita,
K.; Yonemitsu, O. J. Org. Chem. 1990, 55, 7-9. (c) Hikota, M.; Sakurai,
Y.; Horita, K.; Yonemitsu, O. Tetrahedron Lett. 2003, 44, 6367-6370.
(d) Nicolaou, K. C.; Finlay, M. R. V.; Ninkovic, S.; Sarabia, F. Tetrahedron
1998, 54, 7127-7166.
(8) (a) Wender, P. A.; Jankowski, O. D.; Tabet, E. A.; Seto, H. Org. Lett.
2003, 5, 487-490. (b) Wender, P. A.; Jankowski, O. D.; Tabet, E. A.;
Seto, H. Org. Lett. 2003, 5, 2299-2302.
(12) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239-9248.
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15434 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003