Macrocyclization via allyl transfer: Total synthesis of laulimalide [14]

Full text of DOI:10.1021/ja016752q

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10764
J. Am. Chem. Soc. 2001, 123, 10764-10765
Macrocyclization via Allyl Transfer: Total Synthesis
of Laulimalide
Valentin S. Enev,* Hanspeter Kaehlig, and Johann Mulzer*
Institut fu¨r Organische Chemie der UniVersita¨t Wien
Wa¨hringer Strasse 38, A-1090 Wien, Austria
ReceiVed August 2, 2001
Laulimalide (1), a metabolite from various marine sponges,1a-c
stabilizes microtubuli in eukaryotic cells and (along with other
compounds, such as discodermolide,2 eleutherobin,3 and the
epothilones4) has received much attention as a potential successor
of paclitaxel5 in the treatment of hitherto incurable tumors. A
major advantage of 1 may be seen in its unusually high activity
against multidrug resistant cell lines.6 To date, despite a number
of different approaches to individual fragments,7a-j only two total
syntheses have been completed: one by Ghosh and Wang8 and
the second by Mulzer and O¨ hler.9 Both approaches were not
entirely stereocontrolled and made use of well-established mac-
rocylization protocols (i.e. Yamaguchi lactonization and Horner-
type olefination).
In this communication we describe a novel approach to 1 that
features a silicon-mediated allyl transfer macrocyclization as the
key step. Retrosynthetically the carbon skeleton of 1 was to be
assembled from fragments 2 and 3 by generating the Z-2,3-olefin
first and closing the ring by C14,15-bond formation. The
introduction of the 16,17-epoxide was to be performed at the end
via the regio- and stereoselective Sharpless epoxidation described
earlier.9
The synthesis started from commercially available (R) ethyl
hydrogen 3-methylglutarate 4. which was elaborated (Scheme 1)
into methyl ketone 13 in 10 steps with an overall yield of 57%.
The RCM strategy for closing the dihydropyran ring ,which has
been used previously by us7e,f and subsequently by others,7d,h,i
again proved to be the method of choice.
For the introduction of the allyl silane moiety, 13 was converted
into the enolate under kinetic control (KHMDS 1.5 equiv) and
treated with PhNTf2 (1.6 equiv)10 to afford enol triflate 14 as a
single isomer. Next, following Kuwajioma’s protocol,11 compound
14 was subjected to the reaction with TMSCH2MgBr (6 equiv)
in the presence of Pd(PPh3)4 (30 mol %) to give, after 1 h, an
unseparable 1:1 mixture of compound 15 and its ∆12,13-isomers.
Quite obviously, the large amount of the catalyst and the long
reaction time have led to isomerization. The similarity of the
described protocol and the Stille coupling12 prompted us to
perform the reaction in the presence of LiCl. We were pleased to
observe that in the presence of 5 equiv of LiCl and 5 mol % of
Pd(PPh3)4, triflate 14 reacted with TMSCH2MgBr (2 equiv) to
give, after 10 min, pure allyl silane 15 in 96% yield. Removal of
the TES group (K2CO3-MeOH) followed by Dess-Martin oxida-
tion afforded aldehyde 3, which was thus available from 4 in 13
steps and 33% overall yield.
The synthesis of fragment 2 (Scheme 2) began from our
previous intermediate 16,7f which was oxidized to the aldehyde
17. Ketalization with (R,R)-(+)-2,4-pentanediol13 afforded acetal
18 in 98% yield. Removal of the TBDPS group and esterification
of the corresponding alcohol 19 with (CF3CH2O)2P(O)CH2COCl
(1.6 equiv) provided phosphonate 2.
(1) (a) Quin˜oa`, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53, 3642-
3644. (b) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J. J. Org. Chem.
1988, 53, 3644-3646. (c) Jefford, C. W.; Bernardinelli, G.; Tanaka, J.; Higa,
T. Tetrahedron Lett. 1996, 37, 159-161.
Compound 2 was deprotonated (KHMDS, THF) and treated
with aldehyde 3 to give pure Z-enoate 20a in 82% yield.
The cyclization of 20a was performed in 4 × 10-4 M CH2Cl2
solution with 2 equiv of EtAlCl214 and provided macrolide 21 as
a single isomer15 in 82% yield. On monitoring the cyclization by
TLC a transient intermediate was observed that was isolated and
identified as olefin 20b. We thus reasoned that the conversion of
20a into 21 might, in reality, proceed Via two parallel pathways.
One is the direct cyclization of allyl silane 20a. The second
pathway involves first a moisture-induced protodesilylation of 20a
to 20b which then undergoes the cyclization via an ene reaction.
Indeed, when we subjected 20b directly to the macrocyclization
conditions, 21 was obtained in 56% yield, along with 30% of
starting material. In light of these findings the cyclization was
repeated under absolutely anhydrous conditions, now to proceed
without any protodesilylation in 85% yield. To the best of our
(2) Gunasekara, S. P.; Gunasekara, M.; Longley, R. E. J. Org. Chem. 1990,
55, 4912-4915.
(3) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.;
Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744-8745.
(4) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem. 1998,
110, 2120-2153; Angew. Chem., Int. Ed. Engl. 1998, 37, 2014-2045.
(5) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem. 1994, 106,
38-69; Angew. Chem., Int. Ed. Engl. 1994, 33, 15-44.
(6) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarn, A.; Davidson,
B. S. Cancer Res. 1999, 59, 653-660.
(7) (a) Shimizu, A.; Nishiyama, S. Tetrahedron Lett. 1997, 38, 6011-
6014. (b) Shimizu, A.; Nishiyama, S. Synlett 1998, 1209-1210. (c) Ghosh,
A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron Lett. 1997, 38, 2427-2430.
(d) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41, 2319-2322. (e)
Mulzer, J.; Hanbauer, M. Tetrahedron Lett. 2000, 41, 33-36. (f) Dorling, E.
K.; O¨ hler, E.; Mulzer, J. Tetrahedron Lett. 2000, 41, 6323-6326. (g) Dorling,
E. K.; O¨ hler, E.; Mantoulidis, A.; Mulzer, J. Synlett 2001, 1105-1108. (h)
Nadolski, G. T.; Davidson, B. S. Tetrahedron Lett. 2001, 42, 797-800. (i)
Messenger, B. T.; Davidson, B. S. Tetrahedron Lett. 2001, 42, 801-804. (j)
Paterson, I.; Savi, C. D.; Tudge, M. Org. Lett. 2001, 3, 213-216.
(8) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122, 11027-11028.
Tetrahedron Lett. 2001, 42, 3399-3402.
(12) Stille, J. K.; Scott, J. W. J. Am. Chem. Soc. 1986, 108, 3033-3040.
(13) Alexakis, A.; Mangeney, P. Tetrahedron Asymmetry 1990, 1, 477-
511.
(14) Snider, B. B.; Rodini, D. J.; Karras, M.; Kirk, T. C.; Deutsch, E. A.;
Cordova, R.; Price, R. T. Tetrahedron 1981, 37, 3927-3934.
(15) For reactions of allyl transfer to chiral acetals see ref 14 and the
following: (a) Johnson, W. S.; Crackett, P. H.; Elliot, J. D.; Jagodzinski, J.
J.; Lindell, S. D.; Natarajan, S. Tetrahedron Lett. 1984, 25, 3951-3954. (b)
Cambie, R. C.; Higgs, K. C.; Rustenhoven, J. J.; Rutledge, P. S. Aust. J. Chem.
1996, 49, 677-688.
(9) Mulzer, J.; O¨ hler, E. Angew. Chem. In press.
(10) Scott, W.; McMurry, E. Acc. Chem. Res. 1988, 21, 47-59.
(11) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.;
Kusama, H.; Kuwajioma, I. J. Am. Chem. Soc. 1998, 120, 12980-12981.
Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura,
N.; Morihira, K.; Kuwajioma, I. J. Am. Chem. Soc. 2000, 122, 3811-3820.
10.1021/ja016752q CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

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Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 43, 2001 10765
Scheme 1a
Scheme 2a
a Conditions: (a) Dess-Martin oxidation, 96%; (b) (R,R)-(+)-2,4-
pentanediol (1.8 equiv), montmorillonite K-10, toluene, 98%, (c) TBAF,
THF, 82%; (d) (CF3CH2O)2P(O)CH2COCl (1.6 equiv), DMAP, -78 f
0 °C, 98%; (e) KHMDS, -78 °C, 40 min, then 3, 1.2 equiv, 20 min,
82%; (f) EtAlCl2 (2 equiv), -50 f 0 °C, 82%; (g) Dess-Martin
oxidation, 90%; (h) TsOH, CHCl3, 80%; (i) TFA, -78 °C, CH2Cl2, 90%;
(j) Me2BBr, -78 °C, 20 min, 96%.
In conclusion, the first fully stereocontrolled synthesis of
laulimalide has been described. The synthesis is highly convergent
by assembling the molecular skeleton from two comparably sized
fragments 2 and 3 both of which are available from simple chiral
starting materials. The longest linear sequence lists 19 steps with
an overall yield of 21%. Novel features are the macrocyclization
Via competing allyl transfer type reactions and the orthogonality
of two hydroxyl protecting groups, namely MOM and 4-oxo-
pent-2-yl, respectively, which hopefully will allow an easy
differentiation of the two allylic alcohol moieties. At any rate,
the modular structure of our synthesis will make it applicable to
a suitably wide variety of derivatives which will be used to clarify
the pharmacophoric sections of the molecule.
a Conditions: (a) BH3‚Me2S, 99%; (b) Dess-Martin oxidation, 96%;
(c) (-)-Ipc2B-allyl, 87%; (d) Et2NH, EtOH, 98%; (e) acrolein-diethyl-
acetal, TsOH, toluene, 92%; (f) 4 mol % Grubbs catalyst, CH2Cl2, 87%;
(g) TBSO-CHdCH2, LiClO4, 92%; (h) NaBH4, MeOH, 0 °C, 99%; (i)
TESCl, pyridine, 92%; (j) MeLi, Et2O, -75 °C, 90%; (k) KHMDS,
C6H5NTf2, THF, 80%; (l) 5 mol % Pd(PPh3)4, LiCl (5 equiv),
TMSCH2MgBr (2 equiv), Et2O, 96%; (m) K2CO3, MeOH, 0 °C, 98%,
(n) Dess-Martin oxidation 90%.
knowledge, this is the first macrolide formation via allyl transfer,
under conditions so mild that they do not induce the 2,3-Z-E-
isomerization which has been so painfully experienced in other
syntheses.7j,8,9
The removal of the protective groups R1 and R2 required some
care. After oxidation of 21 to ketone 22 it turned out that R1 and
R2 are orthogonal even under acidic conditions, i.e., 22 can be
converted into 22a and 23, respectively. However, on attempting
to transform 22a into 24 with pTsOH complete Z-E-isomerization
of the 2,3-double bond was observed. On the other hand, 23 could
be smoothly deprotected to generate 16,17-deoxy-laulimalide 24,
which was identical (TLC and spectral data) with the compound
obtained previously.9 The conversion of 24 into 1 was performed
via SAE ((+)DIPT, tBuOOH, Ti(OiPr)4 in CH2Cl2) as described
earlier.9
Acknowledgment. This work is dedicated to Professor Manfred
Christl on the occasion of his 60th birthday. It was financially supported
by the Austrian Science Fund (FWF). We thank Mag. M. Hanbauer and
Dr. E. O¨ hler for providing advanced intermediates and additional technical
support.
Supporting Information Available: Spectroscopic data and experi-
mental procedures (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA016752Q