Total synthesis of octalactin A via ring-closing metathesis reaction

Article abstract of DOI:10.1016/S0040-4039(01)02078-0

A new total synthesis of the novel lactone natural product octalactin A is described. The key step involves the facile construction of the eight-membered lactone core via ring-closing metathesis (RCM). This oxocene was elaborated to give the powerful anti

Full text of DOI:10.1016/S0040-4039(01)02078-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 181–184
Total synthesis of octalactin A via ring-closing metathesis
reaction
Keith R. Buszek,* Nagaaki Sato and Youngmee Jeong
Department of Chemistry, Kansas State University, Manhattan, KS 66506-3701, USA
Received 2 October 2001; revised 27 October 2001; accepted 1 November 2001
Abstract—A new total synthesis of the novel lactone natural product octalactin A is described. The key step involves the facile
construction of the eight-membered lactone core via ring-closing metathesis (RCM). This oxocene was elaborated to give the
powerful antitumor agent octalactin A. © 2002 Elsevier Science Ltd. All rights reserved.
Medium-ring systems are found in many biologically and
medicinally active natural products.1 The octalactins2 are
the most important members of a small but fascinating
class of saturated eight-membered ring lactone natural
products that includes cephalosporolide D,3 dregeanin,4
and the putative structures of the gonioheptolides.5
Octalactin A 1 (Fig. 1) in particular is noted for its potent
toxicity against certain human colon cancer cell lines,
among others, and has emerged as a highly promising new
anticancer agent. This activity, combined with its inter-
esting and challenging topology and associated architec-
tural features, continues to generate intense interest from
synthetic organic chemists.6
We published the first total synthesis of the octalactins
by means of an unprecedented and exceptionally facile
and direct lactonization from their corresponding seco
acids.7,8 Although this strategy provided efficient access
to many other similar lactone systems,9 we required a
more flexible entry into the octalactin scaffold. Our
continuing interest in determining the molecular target
and finding the mode of action of octalactin A prompted
us to secure a more expeditious and practical route to this
important compound and its analogues from a common
intermediate.10 The construction of an impressive number
of diverse cyclic structures via the ring-closing metathesis
(RCM) reaction11 prompted us to consider this alternate
approach to the eight-membered lactone systems. In
connection with our early work with the octalactins, we
found that the position of certain stereocenters imposed
conformational constraints on the hydroxy carboxylic
acids that permitted successful lactonization in high
yield.7–9 It occurred to us that these same constraints
might also favor a reactive diene conformation that
affords oxocenes via RCM. We now report that this is
indeed the case and describe the first example of this type
of ring closure in a saturated, monocyclic eight-membered
lactone system (Scheme 1).
Figure 1. Structures of the octalactins.
Scheme 1. RCM with an acyclic diene ester precursor.
* Corresponding author. E-mail: krvb@ksu.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02078-0

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K. R. Buszek et al. / Tetrahedron Letters 43 (2002) 181–184
It should be noted that the oxocene 5, which we have
previously prepared by a much longer and more elabo-
rate route,7 also possesses significant antitumor activ-
ity.10 We reported that this lactone partially blocks the
polymerization of purified tubulin in vitro and may
disrupt microtubule dynamics and therefore work as a
novel mitotic spindle poison.
described above. The alcohol 10 was first protected as
its MPM ether under Lewis acid catalysis conditions14
and the olefin regioselectively hydroborated with 9-
BBN and oxidized to give the desired primary alcohol
11 in 90% yield for the three steps (Scheme 3). Protec-
tion of the alcohol as its MMTr ether followed by
fluoride-induced desilylation with TBAF in THF at 0°C
gave the intermediate alcohol (92%), which was oxi-
dized with Dess–Martin periodinane and the resulting
crude aldehyde immediately subjected to Wittig olefina-
tion to afford the alkene 12 in 85% yield. Hydrolysis of
the MMTr ether followed by Jones oxidation gave the
desired carboxylic acid 13 (82%, two steps). By the
same sequence epi-13 was generated from epi-10.
The synthesis of the alcohol and carboxylic acid com-
ponents of the diene ester precursor to the oxocene 5
began with the methyl (R)- and (S)-3-hydroxy-2-
methylpropionates, respectively. Protection of 6 as its
TBDPS ether followed by DIBAL reduction in diethyl
ether at −78°C provided the alcohol 7 in 87% yield for
two steps (Scheme 2).12 Oxidation of 7 with Dess–Mar-
tin periodinane13 was followed immediately by conden-
sation with vinyl magnesium bromide in THF at −78°C
and slow warming to room temperature to afford a 1:1
mixture of the diastereomers 8 and epi-8 in 92% yield.
Separation by flash chromatography (10% EtOAc:
hexanes) gave the desired intermediate 8.
The components 8 and 13 were esterified with DCC and
DMAP15 to yield the diene ester 3 in 94% yield (Scheme
4). The stage was now set for the key ring closure.
Gratifyingly, the diene underwent RCM cleanly in
refluxing dichloromethane with 10–20 mol% Grubbs
catalyst16 to afford the desired oxocene 2 in 86% yield
after 24 h. Eight-membered rings have long been con-
sidered the most difficult to construct from acyclic
precursors.17 It had been reported that the formation of
eight-membered rings from acyclic precursors and their
The synthesis of the carboxylic acid unit began simi-
larly with the Roche ester antipode 9. The allylic alco-
hols 10 and epi-10 were prepared in the same manner
Scheme 2. Synthesis of the C.6–C.9 segment. Reagents and reaction conditions: (a) TBDPSCl, imidazole, CH2Cl2, rt, 1 h. (b)
DIBAL, Et2O, −78°C. (c) Dess–Martin periodinane, CH2Cl2, rt. (d) (CH2ꢀCH)MgBr, THF, −78°C to rt.
Scheme 3. Synthesis of the C.1–C.5 segment. Reagents and reaction conditions: (a) MPMO(CꢀNH)CCl3/BF3·OEt2/cyclohexane–
CH2Cl2 (2:1)/0°C. (b) 9-BBN, THF, 65°C, then 30% H2O2, 15% NaOH, 0°C. (c) MMTrCl, Et3N, CH2Cl2, rt. (d) TBAF, THF,
rt. (e) Dess–Martin periodinane, CH2Cl2, rt. (f) Ph3PꢀCH2, THF, −78 to 0°C. (g) PPTS, MeOH:THF (1:1). (h) Jones reagent,
acetone, 0°C.

K. R. Buszek et al. / Tetrahedron Letters 43 (2002) 181–184
183
Scheme 4. Synthesis of oxocene 5 via RCM. Reagents and reaction conditions: (a) DCC, DMAP, CH2Cl2, rt, 4 h. (b) Grubbs’
catalyst, CH2Cl2, 40°C, 24 h.
formation via RCM was effective only with additional
cyclic18 or conformational constraints.19 To our knowl-
edge, the formation of 2 represents the first example of
a successful RCM from a simple acyclic diene ester
precursor. The stereocenters presumably restrict bond
angles in a way that leads to a conformation that is
favorably disposed toward RCM. The conformational
effect of quaternary centers in controlling torsional
angles, for example, has been reported.20 Consistent
with this view is the observation that other members of
the octalactin series undergo RCM with varying
degrees of difficulty. It was found for example that the
lactone 14 (derived from 8 and epi-13) experienced ring
closure only with difficulty, while the lactones 15 (from
epi-8 and 13) and 16 (from epi-8 and epi-13) formed
readily via RCM (Table 1). These results are entirely
consistent with that found for the same series in the
lactonization reaction manifold.
C.13 hydroxyl group with the lactone carbonyl. Finally,
oxidative hydrolysis21 of the MPM ether with DDQ
gave (−)-octalactin A 1, whose spectral characteristics
were identical to the naturally derived material.
In conclusion, we have discovered that the synthesis of
the key lactone core of the octalactins via RCM is a
facile process. We believe this to be the first example of
the synthesis of monocyclic eight-membered ring lac-
tones by olefin metathesis chemistry. This method
should find wide applicability to the synthesis of other
medium-ring lactone systems also. The intermediate can
be elaborated to give the octalactins by first extending
the C.7 side chain followed by hydrogenation and
removal of the remaining MPM protecting group. This
novel approach is applicable to the preparation of a
wide range of octalactin analogues as part of a program
to elucidate the mode of action. The results of these
efforts will be reported in due course.
As we have previously reported, reduction of the alkene
in 5 could not be accomplished. This lack of reactivity
presumably reflects severe non-bonded steric interac-
tions. However, by elaborating the C.7 side chain in a
manner previously described7 to that required for octa-
lactin (compound 17, Scheme 5), we found that the
olefin underwent smooth hydrogenation with Pearl-
man’s catalyst and 1 atm of hydrogen. We ascribe this
change in behavior to a more favorable conformation
induced by intramolecular hydrogen bonding of the
Acknowledgement
This research was supported by the National Institutes
of Health COBRE award 1 P20 RR15563, matching
support from the State of Kansas, and Kansas State
University. Acknowledgement is also made to the
American Cancer Society and to the Donors of the
Table 1. Synthesis of octalactin epimers via RCM
Scheme 5. Synthesis of octalactin A.

184
K. R. Buszek et al. / Tetrahedron Letters 43 (2002) 181–184
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for additional support of this
research. The authors are grateful to the reviewers for
helpful suggestions for the improvement of the
manuscript.
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