A divergent approach to apoptolidin and FD-891: Asymmetric preparation of a common intermediate

Article abstract of DOI:10.1016/S0040-4039(03)01173-0

Biologically active Apoptolidin and FD-891 have structural similarity in their macrocyclic cores. Asymmetric preparation of a common intermediate in the total synthesis of these two macrolides is presented. A modified Masuyama Sn-allylation was employed to control the relative stereochemistry in the synthesis of the intermediate.

Full text of DOI:10.1016/S0040-4039(03)01173-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4997–5000
A divergent approach to apoptolidin and FD-891: asymmetric
preparation of a common intermediate
Shu-Sin Chng, Jia Xu and Teck-Peng Loh*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Received 24 March 2003; revised 30 April 2003; accepted 9 May 2003
Abstract—Biologically active Apoptolidin and FD-891 have structural similarity in their macrocyclic cores. Asymmetric prepara-
tion of a common intermediate in the total synthesis of these two macrolides is presented. A modified Masuyama Sn-allylation
was employed to control the relative stereochemistry in the synthesis of the intermediate. © 2003 Elsevier Science Ltd. All rights
reserved.
Apoptolidin (Scheme 1, 1) is a potent apoptosis-induc-
ing agent isolated from Nocardiopsis sp.1,2 It is found to
induce apoptotic cell death selectively in rat glia cells
transformed with the adrenovirus E1A oncogene
(IC50=11 ng/mL). In addition, this 20-membered
macrocyclic lactone is also shown to be an inhibitor of
the mitochondrial F0F1-ATP synthase.3 The interesting
biological activities and novel structure of apoptolidin
make it a challenging target to the synthetic commu-
nity.4 Although the first total synthesis of this natural
product was very recently reported by Nicolaou and
co-workers, the numerous synthetic strategies associ-
ated with this molecule continue to be of great interest.5
In 1994, FD-891 2 was isolated from the fermentation
broth of Streptomyces graminofaciens A-8890.6 This
18-membered macrolide was found to induce morpho-
logical changes of HL-60 cells at low concentrations
and has cytocidal activity against tumor cells in vitro.7
Recently, the absolute stereochemistry of the macrolide
was determined. It has a conjugated ester moiety 4
Scheme 1.
Keywords: apoptolidin; FD-891; divergent synthesis.
* Corresponding author. Fax: (65) 6779 1691; e-mail: chmlohtp@nus.edu.sg
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01173-0

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S.-S. Chng et al. / Tetrahedron Letters 44 (2003) 4997–5000
similar to that found in apoptolidin.8 The structural
similarity in these two natural macrolides suggested a
divergent approach to the synthesis of their macrocyclic
core structures.
mixture of isomers (6a–d, Table 1). The results are
shown in Table 1.
Masuyama has recently reported diastereocontrol in
carbonyl allylation by 1-halobut-2-enes with tin(II)
halides.11 Although the use of tin(II) halide-mediated
allylation also resulted in the cleavage of the protecting
group, modification of the method by the use of tin
metal afforded just two of the possible isomers (6a,b) in
excellent yield and moderate diastereoselectivity, with
the desired isomer 6a as the major product (entry 11,
Table 1). It is clear that with such a system, a non-a-
chelation controlled reaction has taken place to give
complete anti stereochemistry at the newly formed CꢀC
bond. The diastereoselectivity of the allylic methyl rela-
The preparation of 4 began with the synthesis of the
g-homoallylic alcohol 6a, which possesses the desired
absolute stereochemistry at the hydroxyl carbon and
the allylic position. Homoallylic alcohol 6a can be
obtained via a non-a-chelation controlled and syn selec-
tive allylation reaction of chiral aldehyde 5, which in
turn can be easily prepared through a two-step
sequence from commercially available
D-mannitol
(Scheme 2).9
1
The allylation of aldehyde 5 to give homoallylic alcohol
6a was actually quite difficult due to the acid sensitivity
of the acetal-protecting group and the stereoselectivity
which had to be achieved.10 Thus, numerous methods
including tin and indium-mediated reactions to effect
the g-allylation of aldehyde 5 either resulted in the
cleavage of the acetal group or gave a non-selective
tive to the hydroxyl group was found to be 75:25 by H
NMR analysis. Separation of the isomers by silica gel
chromatography (4% ether in hexane) afforded the
desired g-homoallylic alcohol 6a in 68% isolated yield.
The homoallylic alcohol 6a was subsequently protected
as benzyl ether 7 in good yield using benzyl bromide
Scheme 2.
Table 1. Allylation of chiral aldehyde 5

S.-S. Chng et al. / Tetrahedron Letters 44 (2003) 4997–5000
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Scheme 3.
Scheme 4.
The E,E-conjugated ester 4 can be further homologated
through a reduction–oxidation sequence and another
Horner–Emmons–Wittig reaction to afford finally the
E,E,E-conjugated ester 3 (Scheme 4) as one of the key
fragments shown in our retrosynthetic analysis of
apoptolidin.
under basic conditions (Scheme 3). Ozonolytic cleavage
of the terminal olefin in 7 in CH2Cl2 from −78 to −25°C
thus provided the enantiomerically pure aldehyde 8 in
80% yield. Performing the reaction at low temperatures,
including quenching, prevented elimination of the b-
alkoxyl group to form an enone.
Herein, we have reported an efficient synthesis of the
common intermediate in our synthetic approach to
apoptolidin and FD-891. The synthetic pathway is
highlighted by an anti–syn-selective tin-mediated allyla-
tion reaction to control relative stereochemistry. The
extended syntheses of apoptolidin and FD-891 from the
common intermediate are being pursued and results will
be reported in due course.
Two successive Wittig reactions on aldehyde 8 should
eventually bring us to the common intermediate of
interest. However, the easy elimination of the b-alkoxyl
group also gave rise to problems during the formation
of conjugated ester 9. Standard reflux conditions when
reacting (carboethoxyethylidene)triphenylphosphorane
with aldehyde 8 afforded only elimination products. In
the many attempts to overcome the problem, the
Horner–Emmons modification of the Wittig reaction
using a diisopropyl phosphonate ester was successful.12
Therefore, aldehyde 8 reacted with a diisopropyl phos-
phonate ester in the presence of n-butyllithium at
−78°C to give conjugated ester 9 in 70% yield but with
poor E:Z selectivity (55:45). This mixture of E:Z iso-
mers 9 was subjected to a reduction–oxidation sequence
to furnish aldehyde 10 in excellent yield. Fortunately,
the subsequent Wittig reaction of (carboethoxy-
ethyl)triphenylphosphonium bromide with aldehyde
10 in the presence of n-butyllithium at −78°C provided
only the desired E,E-conjugated ester 4 (confirmed
by NOE experiments). Despite the moderate yield of
this final step, the common intermediate 4 in our
synthetic approach to apoptolidin and FD-891 was
successfully synthesized.
Acknowledgements
We gratefully acknowledge the National University of
Singapore for the funding of this research.
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