An improved synthesis of the C15-C28 fragment of laulimalide

Article abstract of DOI:10.1016/S0040-4039(01)02120-7

The C₁₅-C₂₈ fragment of the paclitaxel-like antimicrotubule agent laulimalide has been synthesized in 12 linear steps from known epoxide 5, with an overall yield of 16%. The methyldihydropyran ring of the side chain was efficiently prepared using ring-closing olefin metathesis chemistry. The 19,20-diol stereochemistry originates in starting material 7 and the side chain was appended using a Kocienski-modified Julia coupling.

Full text of DOI:10.1016/S0040-4039(01)02120-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 213–216
An improved synthesis of the C15–C28 fragment of laulimalide
A. Sivaramakrishnan, Geoffry T. Nadolski, Ian A. McAlexander and Bradley S. Davidson*
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA
Received 17 October 2001; revised 31 October 2001; accepted 7 November 2001
Abstract—The C15–C28 fragment of the paclitaxel-like antimicrotubule agent laulimalide has been synthesized in 12 linear steps
from known epoxide 5, with an overall yield of 16%. The methyldihydropyran ring of the side chain was efficiently prepared using
ring-closing olefin metathesis chemistry. The 19,20-diol stereochemistry originates in starting material 7 and the side chain was
appended using a Kocienski-modified Julia coupling. © 2002 Elsevier Science Ltd. All rights reserved.
As part of a program aimed at the discovery of new
antimicrotubule agents, we recently identified the
marine macrolide laulimalide (1)1 as a new paclitaxel
(Taxol™)-like microtubule-stabilizing agent.2 Like
paclitaxel, laulimalide induces the dose-dependent reor-
ganization of cellular microtubules, as well as the for-
mation of abnormal mitotic spindles. It stimulates the
polymerization of tubulin in the absence of polymeriza-
tion promoters such as glycerol and GTP. Laulimalide
is a potent inhibitor of cellular proliferation with IC50
values in the low nanomolar range against drug sensi-
tive cell lines and, in contrast to paclitaxel, it retains
activity against SKVLB-1 cells, a P-glycoprotein over-
expressing multidrug resistant ovarian cancer cell line,
suggesting that it is a poor substrate for transport by
P-glycoprotein. Furthermore, laulimalide triggers apop-
totic cell death. Laulimalide, therefore, represents a new
class of microtubule-stabilizing agent, with activities
that may prove therapeutically useful, placing it within
an exclusive group of compounds that, in addition to
the taxanes, includes only the marine metabolites
discodermalide3 and eleutherobin4 and the microbial
metabolites the epothilones.5
Laulimalide has attracted significant recent attention
from synthetic organic chemists, with five groups hav-
ing published a total of 16 papers describing their
synthetic efforts related to laulimalide.6 The first total
synthesis of laulimalide was reported,6h along with a
follow-up paper describing an improved macrocycliza-
tion approach,6l by the Ghosh group. Additional com-
pleted syntheses have now been published by the
Mulzer6o and Paterson groups.6p In this communica-
tion, we would like to describe our second generation
synthesis of the C15–C28 portion of laulimalide.
Our revised retrosynthetic analysis is shown in Scheme
1. It involves dividing the C15–C28 fragment (2) into
two pieces, aldehyde 3 (C15–C21) and sulfone 4 (C22–
C28), which we proposed to connect via a Julia/Kocien-
ski coupling reaction.7 Fragment 3 was to be prepared
in a straightforward manner from known epoxide 5,8
Scheme 1. Retrosynthetic analysis.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02120-7

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A. Si6aramakrishnan et al. / Tetrahedron Letters 43 (2002) 213–216
available in seven steps from
L
-ascorbic acid.9 Sulfone 4
Still, although the initial oxidation of the sulfide to a
is available from diene 6, an intermediate in our previ-
ous synthesis,6k using ring-closing olefin metathesis
chemistry.10 This approach differs from our previous
synthesis in several important ways: (1) it targets the
19R-epimer necessary for application of a Mitsunobu
macrocyclization reaction, as reported by Paterson;6h
sulfoxide was extremely facile, further oxidation to give
sulfone 4 proved quite difficult. In fact, over oxidation
of the alkene in 4 to the epoxide (12) was competitive
with sulfoxide oxidation, typically yielding a mixture of
sulfoxide, sulfone (4), and epoxysulfone (13) products.
Fortunately, treatment of 12 with PPh3/I2 cleanly con-
verted the epoxide back to the desired alkene.13 Thus,
the ammonium molybdate catalyzed oxidation was
allowed to run until the sulfoxide was completely con-
sumption, giving a 1.1:1 ratio of 4:12, the later of which
could be recycled back to sulfone 4, ultimately giving
an 80% yield of sulfone, from 11.
(2) the starting material (5 or L-ascorbic acid) contains
the stereochemical information necessary for both the
C19 and C20 chirality centers; and (3) the epoxide is
incorporated early in order to direct the asymmetric
allylation reaction to be used for coupling the two
major fragments of the molecule.
The synthesis of fragment 3 is outlined in Scheme 2.
Opening of the epoxide with the anion generated from
TBPS propargyl ether gave 7, which was converted into
aldehyde 3 via a series of protection and deprotection
steps. Protection of the secondary alcohol as its PMB
ether is followed by acetonide deprotection11 to give
diol 8. Selective pivaloylation of the primary alcohol,
silylation of the secondary alcohol, pivaloate ester
reduction, and Swern oxidation gave compound 3.
The coupling of fragments 3 and 4 (Scheme 4) was
accomplished using the Kocienski-modified Julia cou-
pling procedure.7 Our initial attempt involved deproto-
nation of sulfone 4 with KHMDS in DME followed by
addition of aldehyde 3, giving the crude product in a
respectable 80% yield, but with a disappointing 1:1.3
trans:cis isomeric ratio. Fortunately, substituting DMF
for DME provided the product in an equivalent 81%
yield, but with an improved 5:1 trans:cis ratio. Selective
removal of the TBPS group with NaOH in refluxing
MeOH14 yielded a propargylic alcohol that was reduced
with Red-Al14 to give allylic alcohol 14. A Sharpless
asymmetric epoxidation reaction15 provided the epoxy-
alcohol, which could be oxidized to give the C15–
C28 fragment of laulimalide (2).16
The synthesis of sulfone 4 (Scheme 3) started with diene
6, available in three steps from (R)-glycidol, as previ-
ously described.6k Ring closing olefin metathesis and
deprotection gives alcohol 10, which can be coupled
with 1-phenyl-1H-tetrazole-5-thiol under Mitsunobu
conditions to give sulfide 11. The oxidation of the
sulfide to the desired sulfone, however, proved trouble-
some. A survey of the usual oxidizing agents, showed
In summary, we have reported an improved synthesis
of the C15–C28 fragment of the microtubule-stabilizing
agent laulimalide. Salient features include: (1) the use
12
ammonium molybdate/H2O2 to give the best results.
Scheme 2. (a) TBPSOCH2CꢀCH/n-BuLi, THF, BF3–OEt2, −78°C (82%); (b) (i) PMB–Br, KHMDS, DMF, 0°C, (ii) 1,3-
propanedithiol (6 equiv.), BF3–OEt2, −78°C (71% over two steps); (c) (i) (CH3)3COCl, Et3N, CH2Cl2 (93%), (ii) TIPS–OTf,
2,6-lutidine, DMF (95%); (d) (i) DIBALH, CH2Cl2, −78°C (98%), (ii) (COCl)2, DMSO, −78°C, then Et3N, −78°C to rt (88%).
Scheme 3. (a) (i) Grubbs’ catalyst, CH2Cl2, (95%), (ii) TFA, MeOH (81%); (b) DIAD, PPh3, 1-phenyl-1H-tetrazole-5-thiol (85%);
(c) (NH4)6Mo7O24, H2O2, EtOH (4, 45%; 13, 40%); (d) PPh3, I2, CH3CN (87%).

A. Si6aramakrishnan et al. / Tetrahedron Letters 43 (2002) 213–216
215
Scheme 4. (a) KHMDS, DMF, then 3 (81%; 5:1, trans:cis); (b) (i) 10% NaOH in MeOH, reflux (87%), (ii) Red-Al, ether (85%);
(c) (i) (+)-DIPT, TBHP (84%; 85% d.e.), (ii) (COCl)2, DMSO, −78°C, Et3N, −78°C to rt (85%).
RCM chemistry for the preparation of the terminal
dihydropyran ring; (2) the incorporation of both the
C19 and C20 stereochemistries in the starting material;
and (3) the application of a Julia/Kocienski coupling
for the successful addition of the dihydropyran side
chain. Further work toward the synthesis of laulimalide
is underway.
Tudge, M. Org. Lett. 2001, 3, 213–216; (j) Nadolski, G.
T.; Davidson, B. S. Tetrahedron Lett. 2001, 42, 797–800;
(k) Messenger, B. T.; Davidson, B. S. Tetrahedron Lett.
2001, 42, 801–803; (l) Ghosh, A. K.; Wang, Y. Tetra-
hedron Lett. 2001, 42, 3399–3401; (m) Dorling, E. K.;
Ohler, E.; Mantoulidis, A.; Mulzer, J. Synlett 2001, 1105–
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Y. C. Bull. Kor. Chem. Soc. 2001, 22, 791–792; (o)
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Acknowledgements
7. (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.;
Morley, A. Synlett 1998, 26–28; (b) Kocienski, P. J.; Bell,
A.; Blakemore, P. R. Synlett 2000, 365–366.
We thank the National Institutes of Health (CA81388),
the Department of Defense (DAMD17-00-1-0480), and
Utah State University for financial support of this
research
8. Le Merrer, Y.; Gravier-Pelletier, C.; Dumas, J.; Depezay,
J. C. Tetrahedron Lett. 1990, 31, 1003–1006.
9. Although based upon the methods reported in Ref. 8, the
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16. Selected data for compound 2: 1H NMR l 8.87 (1H,
d, J=6.3 Hz), 7.24 (2H, d, J=8.6 Hz), 6.84 (2H, d,
J=8.6 Hz), 5.73 (2H, m), 5.41 (1H, brs), 4.71 (1H, d,
J=11.4 Hz), 4.43 (1H, d, J=11.4 Hz), 4.38 (1H, m),
4.16 (2H, m), 4.02 (1H, dt, J=9.9, 3.3 Hz), 3.54 (1H,
dt, J=8.4, 3.3), 3.26 (1H, ddd, J=6.2, 5.2, 1.9 Hz),
3.06 (1H, dd, J=6.2, 1.9 Hz), 2.07 (1H, ddd, J=14.6,
8.7, 5.1 Hz), 2.03 (1H, m), 1.89 (1H, brd, 16.7 Hz),
1.70 (3H, s), 1.66 (1H, ddd, J=14.6, 6.3, 3.8 Hz); 13C
NMR l 198.1, 159.3, 133.0, 131.2, 130.6, 130.3, 129.6,
119.79, 113.8, 80.2, 75.6, 73.3, 72.3, 65.5, 59.0, 55.0,
55.0, 35.5, 32.4, 22.9, 18.1, 12.4; HRFABMS (MNBA+
NaI) calcd for C31H48NaO6Si: 567.3118; found: 567.
3105.