Total synthesis of neolaulimalide and isolaulimalide

Article abstract of DOI:10.1021/ol802075v

(Chemical Equation Presented) The first total syntheses of the potential antitumoral leads neolaulimalide (2) and isolaulimalide (3) have been achieved. Key steps in our convergent, fully stereocontrolled route are a Yamaguchi macrolactonization, a Julia-Lythgoe-Kocienski olefination, a Kulinkovich reaction, and a cyclopropyl-allyl rearrangement to install the exo-methylene group. Overall, we synthesized 2 in 21 linear steps (3% yield) and 3 in 24 steps (2% yield).

Full text of DOI:10.1021/ol802075v

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4701-4704
Total Synthesis of Neolaulimalide and
Isolaulimalide†
Andreas Gollner and Johann Mulzer*
Institut fu¨r Organische Chemie, UniVersita¨t Wien, Wa¨hringerstrasse 38,
1090 Vienna, Austria
johann.mulzer@uniVie.ac.at
Received September 4, 2008
ABSTRACT
The first total syntheses of the potential antitumoral leads neolaulimalide (2) and isolaulimalide (3) have been achieved. Key steps in our
convergent, fully stereocontrolled route are a Yamaguchi macrolactonization, a Julia-Lythgoe-Kocienski olefination, a Kulinkovich reaction,
and a cyclopropyl-allyl rearrangement to install the exo-methylene group. Overall, we synthesized 2 in 21 linear steps (3% yield) and 3 in 24
steps (2% yield).
Laulimalide (1), neolaulimalide (2), and isolaulimalide (3)
are isomeric polyketide macrolides which have been
isolated from the marine sponge Fasciospongia rimosa
in 1995.1c 1 and 3 were also found in various other
sponges.1 All three isomers stabilize microtubuli similar
to paclitaxel, epothilone, discodermolide, and others.2 1
and 2 inhibit proliferation of several tumor cell lines with
IC50 values in the low nanomolar range,1c whereas the
In relation to 3 (Scheme 1), 1 is an intrinsically unstable
compound. On exposure to acid, 1 rearranges to 3 within
2 h via an acid-catalyzed SN2-type attack of the C20 hydroxyl
group on the C17 position of the epoxide.1b 2 shows an
appreciably reduced lability toward acid. First it undergoes
(4) (a) Liu, J.; Towle, M. J.; Cheng, H.; Saxton, P.; Reardon, C.; Wu,
J.; Murphy, E. A.; Kuznetsov, G.; Johannes, C. W.; Tremblay, M. R.; Zhao,
H.; Pesant, M.; Fang, F. G.; Vermeulen, M. W.; Gallagher, B. M., Jr.;
Littlefield, B. A. Anticancer Res. 2007, 27, 1509. (b) Johnson, T. A.; Tenney,
K.; Cichewicz, R. H.; Morinaka, B. I.; White, K. N.; Amagata, T.;
Subramanian, B.; Media, J.; Mooberry, S. L.; Valeriote, F. A.; Crews, P.
J. Med. Chem. 2007, 50, 3795.
activity of
3
is significantly lower (micromolar
range).1c,2-4
(5) (a) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122, 11027.
(b) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973. (c)
† Dedicated to the memory of Dr. Marion Ko¨gl.
¨
(1) (a) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53, 3642.
(b) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul, V. J. J.
Org. Chem. 1988, 53, 3644. (c) Higa, T.; Tanaga, J.-i.; Bernadinelli, G.;
Jefford, C. W. Chem. Lett. 1996, 255.
Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40, 3842. (d) Paterson,
I.; De Savi, C.; Trude, M. Org. Lett. 2001, 3, 3149. (e) Mulzer, J.; Enev,
V. S.; Kaehlig, H. J. Am. Chem. Soc. 2001, 123, 10764. (f) Wender, P. A.;
Hegde, S. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124,
4956. (g) Williams, D. R.; Liang, M.; Mullins, R. J.; Stites, R. E.
Tetrahedron Lett. 2002, 43, 4841. (h) Mulzer, J.; Ahmed, A.; Hoegenauer,
(2) (a) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarm, A.;
Davidson, B. S. Cancer Res. 1999, 59, 653. (b) Gallagher, B. M., Jr. Curr.
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E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.; Ohler, E. J. Org. Chem.
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Wang, Y.; Kabaki, M.; Jung, M. K.; Andreu, J. M.; Ghosh, A. K.;
Giannakakou, P.; Hamel, E. Biochemistry 2002, 41, 9109. (b) Gaitanos,
T. N.; Buey, R. M.; Diaz, F. J.; Northcote, P. T.; Teesdale-Spittle, P.;
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10.1021/ol802075v CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

Scheme 1
.
Laulimalides
Scheme 2. Retrosynthetic Analysis
ring contraction to 1, which then isomerizes to 3 as expected.
After two days, the rearrangement is complete.1c The total
synthesis of 15 (and biologically active analogues thereof)5k,6
has gripped the synthetic community for over a decade now.
However, since acid lability has been identified as a major
drawback in deleloping 1 as an anticancer drug,6a 2 and 3
should be considered as more promising alternative lead
compounds. Compound 2 has only been isolated once, and
surprisingly, no total syntheses of 2 (and/or 3) have been
reported to date. Consequently, we decided to develop
efficient, flexible, stereocontrolled routes to both 2 and 3, to
enable advanced biological studies.
three steps. Evans alkylation of N-propionyl-oxazolidinone
10 with 9 followed by reduction with LiBH4 provided alcohol
11 which was converted into the nitrile by either a Mitsunobu
reaction9 or, for a larger scale, by tosylation and SN2
displacement with sodium cyanide. Reduction of the nitrile
with DIBALH delivered aldehyde 12 which was treated with
(-)-Ipc-allylborane to yield homoallylic alcohol 13 in 95%
yield and 16:1 dr.10 For streamlining the conversion of 13
into dihydropyran 14, installation of the C-2/3 side chain
As shown in Scheme 2, a key step in our syntheses is the
Julia-Kocienski olefination of aldehyde 5 and sulfone 6.
The preparation of fragment 5 (Scheme 3) started from
commercially available diol 7 which can be obtained from
natural (S)-malic acid in two steps.7 After protection of the
alcohols as TBS-ethers, we used a Kulinkovich reaction8 to
generate cyclopropanol 8 which was directly used in the next
step. Mesylation and treatment of the crude product with
MgBr2·OEt2 inrefluxingCH2Cl2 resultedinacyclopropyl-allyl
rearrangement8 furnishing allylbromide 9 in 73% yield over
Scheme 3. Synthesis of Fragment 5
(6) (a) Wender, P. A.; Hegde, S. G.; Hubbard, R. D.; Zhang, L.;
Mooberry, S. L. Org. Lett. 2003, 5, 3507. (b) Paterson, I.; Bergmann, H.;
Menche, D.; Berkessel, A. Org. Lett. 2004, 6, 1293. (c) Mooberry, S. L.;
Randall-Hlubek, D. A.; Leal, R. M.; Hegde, S. G.; Hubbard, R. D.; Zhang,
L.; Wender, P. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8803. (d)
Gallagher, B. M., Jr.; Zhao, H.; Pesant, M.; Fang, F. G. Tetrahedron Lett.
2005, 46, 923. (e) Paterson, I.; Menche, D.; Hakansson, A. E.; Longstaff,
A.; Wong, D.; Barasoain, I.; Buey, R. M.; Diaz, J. F. Bioorg. Med. Chem.
Lett. 2005, 15, 2243. (f) Wender, P. A.; Hilinski, M. K.; Soldermann, N. G.;
Mooberry, S. L. Org. Lett. 2006, 8, 1507. (g) Wender, P. A.; Hilinski, M. K.;
Skaanderup, P. R.; Soldermann, N. G.; Mooberry, S. L. Org. Lett. 2006, 8,
4105. (h) Faveau, C.; Mondon, M.; Gesson, J. P.; Mahnke, T.; Gebhardt,
S.; Koert, U. Tetrahedron Lett. 2006, 47, 8305
.
(7) Saito, S.; Ishikawa, T.; Kurada, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067.
(8) (a) Kulinkovich, O. G.; Kozyrkov, Y. Y.; Bekish, A. V.; Matiush-
enkov, E. A.; Lysenko, I. L. Synthesis 2005, 10, 1713. For reviews, see:
(b) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789. (c)
Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597.
(9) (a) Wilk, B. Synth. Commun. 1993, 23, 2481. (b) Tsunoda, T.;
Uemoto, K.; Nagino, C.; Kawamura, M.; Kaku, H.; Ito, S. Tetrahedron
Lett. 1999, 40, 7355.
(10) Brown, H. C.; Jadhav, P. K.; Bhat, K. S.; Perumal, T. J. Org. Chem.
1986, 51, 432.
4702
Org. Lett., Vol. 10, No. 20, 2008

and RCM were performed successively in one pot.5h,11
Aldehyde 14 was transformed into the terminal alkyne with
the Bestmann-Ohira reagent.12 The primary TBS ether was
cleaved selectively, and the resulting alcohol was oxidized
to aldehyde 5.
Scheme 5. Synthesis of 2
The syntheses of 6a and 6b (Scheme 4) started with the
removal of the TES-ether from intermediate 175hwith HF-
Scheme 4. Synthesis of 4a,b
with 4% of the dimer.16 The OTBS group was easily
desilylated in the next step to give 21, and what appeared a
simple endgame turned out to be a highly delicate operation.
For, on attempting to remove the 19-OPMB protecting group,
we had not realized how strong the driving force would be
to restore the more favorable 20-membered lactone. In fact,
under standard conditions (excess of DDQ, phosphate buffer,
pH 7), PMB removal was ensued by rapid acyl migration,
and macrolactone 22 was isolated as the sole product. Model
inspection, however, gave us a hint that the ring strain which
obviously disfavors the larger macrolide would be much
reduced in the (Z)-enoate. Hence, Lindlar reduction to give
23 was performed prior to the crucial oxidative PMB
removal. To our delight, ultrasound treatment of 23 with
DDQ under strictly neutral conditions during reaction and
workup gave desoxyneolaulimalide (24) in excellent yield.
It turned out that 24 was acid sensitive indeed; however, its
trans-acylation to desoxylaulimalide was much more ac-
celerated by base. Therefore, in the last step we used the
Sharpless epoxidation (SAE) with a modified, nonbasic
workup and obtained 2 in 73% yield. All analytical data of
2 were in full accord with the ones reported.1c
For the synthesis of 3 (Scheme 6), TBS ether 4b was
deprotected, and SAE of the resulting allylic alcohol yielded
epoxide 25. After extensive experimentation, we found that
on removing the OMOM protecting group with BF3·OEt2
and PhSH intramolecular opening of the epoxide occurred
to give the tetrahydrofuran in 70% yield. Protection of the
resulting diol as TBS ethers led to compound 26. Oxidative
PMB deprotection and C-1 elongation delivered seco acid
27. Model inspection indicated that macrolactonization would
not be facile, due to the transannular strain exerted by the
rigid tetrahydrofuran ring. Under these circumstances, we
pyridine to give the primary alcohol selectively which was
immediately transformed into sulfide 18 (90% over two steps)
by treatment with 1-phenyl-1H-tetrazol-5-thiol under Mit-
sunobu conditions. Luche reduction of 18 at low temperatures
delivered the syn-product 19 in almost quantitative yield and
good diastereoselectivity (dr > 17:1),13 from which 6a and
6b were prepared by protection of the free alcohol as a TES-
and MOM-ether, respectively, and oxidation to the sulfones.
The Julia-Kocienski olefination14 of aldehyde 5 with
sulfones 6a,b in THF at -78 °C delivered olefins 4a,b with
complete E-selectivity.
For the synthesis of 2 (Scheme 5), removal of the TES
ether from alkyne 4a and C-1 elongation to seco acid 20
were performed in one pot. Yamaguchi lactonization15
furnished the 21-membered macrolactone in 35% yield along
(11) For reviews, see:(a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1998, 371. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (d) Grubbs, R. H.;
Trinka, T. M. Acc. Chem. Res. 2001, 34, 18
.
(12) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Bestmann, H. J.;
Mu¨ller, S.; Liepold, B.; Roth, G. J. Synlett 1996, 521. (c) Bestmann, H. J.;
Mu¨ller, S. G.; Liepold, B.; Roth, G. J. Synthesis 2004, 1, 59.
(13) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(14) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, P. J.
Synlett 1998, 26. For a review, see: (b) Blakemore, P. R. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563.
(15) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 51, 1989.
(16) Classical Yamaguchi conditions in very high dilution at rt gave
best results, while “modified Yamaguchi conditions” promoted formation
of the dimer. For a review see: Parenty, A.; Moreau, X.; Campagne, J.-M.
Chem. ReV. 2006, 106, 911.
Org. Lett., Vol. 10, No. 20, 2008
4703

28 could be easily isolated by chromatography. Reduction
of the triple bond to the (Z)-enoate gave 3 which was
identical with the sample we obtained from 1 by treatment
with a catalytic amount of acid. All analytical data of 3
matched those in the literature.1
Scheme 6. Synthesis of 3
In conclusion, we have described the first total syntheses
of neolaulimalide (2) (21 steps over the longest linear
sequence in 3% overall yield) and of isolaulimalide (3) (24
linear steps, 2% yield). The synthesis of 2 is essential for
the re-evaluation of its promising biological properties since
the compound has not been reisolated since its original
discovery. The route to 3 could prove of value for the
preparation of late-step analogues, as the polyfunctional
intermediate 26 is fully stable and could be modified in many
ways.
Acknowledgment. We gratefully acknowledge financial
support from The Austrian Science Fund (FWF project L202-
N19). We thank Dr. H. Ka¨hlig, Dr. L. Brecker, and S.
Felsinger, Universita¨t Wien, for NMR spectra and M. Zinke
and S. Schneider, Universita¨t Wien, for HPLC analysis.
Supporting Information Available: Experimental pro-
cedures and analytical and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
were pleased to obtain, again under Yamaguchi conditions,
the desired macrolactone in 38% yield, along with 9% of
the dimer.15,16 This mixture was hard to separate; however,
after removal of the TBS-protecting groups the monomer
OL802075V
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Org. Lett., Vol. 10, No. 20, 2008