Synthetic studies toward the microtubule-stabilizing agent laulimalide: Synthesis of the C15-C28 fragment

Article abstract of DOI:10.1016/S0040-4039(00)02115-8

The C₁₅-C₂₈ fragment of the paclitaxel-like antimicrotubule agent laulimalide has been synthesized in 12 linear steps with an overall yield of 14%. The methyldihydropyran ring of the side chain was efficiently prepared using ring-clo

Full text of DOI:10.1016/S0040-4039(00)02115-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 801–803
Synthetic studies toward the microtubule-stabilizing agent
laulimalide: synthesis of the C15–C28 fragment
B. Travis Messenger and Bradley S. Davidson*
Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, USA
Received 16 November 2000; accepted 17 November 2000
Abstract—The C15–C28 fragment of the paclitaxel-like antimicrotubule agent laulimalide has been synthesized in 12 linear steps
with an overall yield of 14%. The methyldihydropyran ring of the side chain was efficiently prepared using ring-closing olefin
metathesis chemistry and the 19,20-syn-diol was generated through the addition of a mixed vinyl zincate to a protected
a-hydroxyaldehyde. © 2001 Published by Elsevier Science Ltd.
within an exclusive group of compounds that, in addi-
As part of a program aimed at the discovery of new
tion to the taxanes, includes only the marine metabo-
antimicrotubule agents, we recently identified the
lites discodermolide3 and eleutherobin4 and the
marine macrolide laulimalide (1)1 as a new paclitaxel
microbial metabolites the epothilones.5
(Taxol™)-like microtubule-stabilizing agent.2 Like pa-
clitaxel, laulimalide induces the dose-dependent reorga-
nization of cellular microtubules, as well as the
formation of abnormal mitotic spindles. It stimulates
the polymerization of tubulin in the absence of polymer-
ization promoters such as glycerol and GTP. Lauli-
malide is a potent inhibitor of cellular proliferation with
IC50 values in the low nanomolar range against drug
sensitive cell lines and, in contrast to paclitaxel, it
retains activity against SKVLB-1 cells, a P-glycoprotein
overexpressing multidrug resistant ovarian cancer cell
line, suggesting that it is a poor substrate for transport
by P-glycoprotein. Furthermore, laulimalide triggers
apoptotic cell death. Laulimalide, therefore, represents
a new class of microtubule-stabilizing agent, with activ-
ities that may prove therapeutically useful, placing it
Considering its potent biological activity and interesting
structure, laulimalide has attracted surprisingly little
interest from synthetic organic chemists. Three groups
have published a total of seven papers describing their
synthetic efforts related to laulimalide,6,7 including five
reports of syntheses of the C1–C16 portion of the
macrocyclic ring and two reports of a preparation of
the C12–C29 fragment of the molecule.6a–c In addition,
we recently completed a hetero Diels–Alder approach
to the preparation of the C20–C26 side chain of lauli-
malide,8 and in the adjoining paper we describe a
synthesis of the C1–C14 segment of laulimalide.9 In this
communication, we would like to describe our approach
to the synthesis of the C15–C28 portion of laulimalide.
O
BzO
CHO
OPMB
O
OH
O
O
H
OTIPS
O
15
19
O
H
27
OH
23
O
5
3
OH
H
OHC
+
1
H
OPMB
O
H
I
O
2
1
HO
O
4
6
Scheme 1. Retrosynthetic analysis.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02115-8

802
B. T. Messenger, B. S. Da6idson / Tetrahedron Letters 42 (2001) 801–803
secondary alcohol (99%) that was converted to its allyl
ether 11 with allyl bromide/KH (99%). After cleavage
of the trityl group with TFA in CH2Cl2 (71%), the
primary alcohol was oxidized to aldehyde 12 (92%).
The diene aldehyde was then subjected to RCM condi-
tions using Grubbs’ catalyst,12 cleanly providing ring-
closed product 13 in 66% yield. Vinyl iodide 4 was then
obtained using Takai’s iodoolefination reaction,14 albeit
in low yield (48%) after purification from a 6:1 mixture
of trans:cis isomers.
Our retrosynthetic analysis is shown in Scheme 1. Con-
sidering the lability of the epoxide group, we envisioned
its incorporation late in the synthesis. Our strategy
involves dividing the C15–C28 fragment (2) into two
pieces, 3 (C15–C20) and 4 (C21–C28), which we proposed
to couple via the chelation-controlled addition of a
vinyl anion generated from 4 to the aldehyde of 3.10
Fragment 3 was to be prepared in a straightforward
manner from commercially available (S)-(−)-b-
hydroxy-g-butyrolactone 5,11 while fragment 4 was to
be constructed from (R)-glycidol 6, using ring-closing
olefin metathesis chemistry.12
Completion of fragment 2 (Scheme 4) was accom-
plished using the zinc-catalyzed, chelation-controlled
addition of a vinyl anion formed from 4 to the aldehyde
of compound 3.10 The sequential transmetallation of
vinyl iodide 4 with tert-BuLi followed by ZnMe2
yielded a mixed zincate species (i.e. 14), which was then
added to a mixture of 3 and ZnMe2. While the reaction
yielded exclusively the syn-diol stereochemistry (see
below), the desired product 15 was unexpectedly con-
taminated with approximately 25% of methyl adduct
16, presumably resulting from the transfer of methyl
from a zincate species formed from excess tert-BuLi
and ZnMe2.15 Attempts to reduce the amount of tert-
BuLi or to perform the initial halogen–metal exchange
with n-BuLi led to lower yields and more complex
mixtures. Because 15 and 16 were difficult to separate
chromatographically, the mixture was treated with
TIPS triflate, followed by DIBAL to give a mixture of
primary alcohols that were chromatographically sepa-
The synthesis of fragment 3 is outlined in Scheme 2.
Treatment of 5 with PMB–trichloroacetimidate13 and
BF3–OEt2 provided the protected lactone. Reduction
with one equivalent of DIBAL gave hemiacetal 7
(99%), which was treated directly with methyl
(triphenylphosphoranylidene)acetate in benzene, yield-
ing unsaturated ester 8 in 90% yield. The protection of
the primary alcohol as its TBS ether (99%) was fol-
lowed by reduction of the ester (97%), and protection
of the resulting alcohol as its benzoate ester, giving
fully protected 9 in 82% yield. Finally, treatment of 9
with TBAF provided a primary alcohol (63%) that was
oxidized to give fragment 3 (88%).
The synthesis of fragment 4 (Scheme 3) started with the
copper(I)-catalyzed addition of isopropenylmagnesium
bromide to trityl-protected (S)-glycidol 10, to give a
OH
OTBS
O
a, b
c
d, e, f
g, h
BzO
5
3
MeO2C
HO
OPMB
OPMB
OPMB
7
8
9
Scheme 2. (a) PMB–trichloroacetimide, BF3–OEt2, CH2Cl2, −78°C, 1 h (76%); (b) DIBAL, toluene, −78°C, 5 min (99%); (c)
Ph3PꢀCHCO2Me, PhH, reflux, 1 h (90%); (d) TBSCl, Et3N, DMAP, CH2Cl2, 2 h (99%); (e) DIBAL, toluene, −78°C, 2 h (97%);
(f) PhCOCl, pyridine, DMAP, CH2Cl2, rt, 16 h (82%); (g) TBAF, THF, rt, 2 h (63%); (h) (COCl)2, DMSO, −78°C; then Et3N,
−78°C to rt (88%).
H
OHC
O
O
OHC
O
e
a, b
c, d
f
tritylO
tritylO
O
4
12
10
11
13
Scheme 3. (a) CH3C(MgBr)ꢀCH2, CuI, THF, −30°C, 1 h (99%); (b) KH, allyl bromide, THF, 30 min (99%); (c) 10% TFA in
MeOH, rt, 3 h (65%); (d) (COCl)2, DMSO, −78°C; Et3N, −78°C to rt (92%); (e) Cl2(PCy3)2RuꢀCHPh, CH2Cl2, rt, 2 days (66%);
(f) CHI3 (3 equiv.), CrCl2 (9 equiv.), THF, 0°C, 3.5 h (6:1, trans:cis; 48% trans).
OH
OH
H
H
BzO
O
BzO
O
LiMe2Zn
a
b
+
4
OPMB
OPMB
15
16
14
OTIPS
H
HO
O
c, d
e
13
2
OPMB
17
Scheme 4. (a) tert-BuLi (1.6 equiv.), ether, −78°C, then ZnMe2; (b) 3, ZnMe2, ether (60%, 3:1 ratio of 13:14); (c) TIPSOTf,
2,6-lutidine, CH2Cl2 (67%); (d) DIBAL, CH2Cl2, −78°C (82%); (e) (COCl)2, DMSO, −78°C; Et3N, −78°C to rt (99%).

B. T. Messenger, B. S. Da6idson / Tetrahedron Letters 42 (2001) 801–803
803
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by oxidation of the alcohol to an aldehyde.
The stereochemistry of the newly introduced C20 chiral
center was confirmed by a-methoxy-a-phenylacetic acid
(MPA) ester analysis.17 Esterification of separate
aliquots of the 15/16 mixture with (R)-MPA and (S)-
MPA using DCC as the coupling reagent led to the
corresponding diastereomeric (R)- and (S)-esters,
1
respectively, which were analyzed by H NMR spec-
troscopy. Although complicated by significant signal
overlap, several diagnostic NMR signals could be
assigned and used for the stereochemical determination.
1
Specifically, when H NMR spectra recorded for the
(R)- and (S)-MPA esters were compared, it could be
clearly observed that the H16 and H17 olefinic protons
were shifted more upfield in the spectrum recorded for
the (S)-MPA ester and the signals assigned to the H21
and H22 olefinic protons appeared more upfield in the
spectrum of the (R)-MPA ester. Using the model elabo-
rated by Trost,17 these results support the assignment of
the C20 chiral center as S, confirming the formation of
the desired syn-diol geometry.
In summary, we have reported a new synthesis of the
C15–C28 fragment of the microtubule-stabilizing agent
laulimalide. Our approach utilized RCM chemistry for
the preparation of the terminal dihydropyran ring and
a Zn-catalyzed addition of a vinyl anion to an a-
alkoxyaldehyde for the coupling of fragments 3 and 4
and the formation of the syn-diol. Further work toward
the synthesis of laulimalide is underway.
9. Nadolski, G. T.; Davidson, B. S. Tetrahedron Lett.,
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Acknowledgements
We thank the National Institutes of Health (CA81388)
and Utah State University, through a New Faculty
Research Grant, for support of this research. Mass
spectrometry was provided by the Washington Univer-
sity Mass Spectrometry Resource with support from
the NIH National Center for Research Resources
(P41RR0954).
15. Laloe, E.; Srebnik, M. Tetrahedron Lett. 1994, 35, 5587–
5590.
16. Compound 2: [h]D20 −55.4 (c 0.5, CH2Cl2); IR (film) wmax
1
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