Enantioselective total synthesis of peloruside a: A potent microtubule stabilizer

Article abstract of DOI:10.1021/ol703091b

An enantioselective total synthesis of (+)-peloruside A (1) is described. Peloruside A (1) is a potent microtubule stabilizer with significant clinical potential. The synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C24 segment 3 by a novel aldol protocol followed by Yamaguchi macrolactonization of the resulting seco-acid, selective methylation of hemi-ketal and removal of the protecting groups to peloruside A.

Full text of DOI:10.1021/ol703091b

ORGANIC
LETTERS
2008
Vol. 10, No. 5
1001-1004
Enantioselective Total Synthesis of
Peloruside A: A Potent Microtubule
Stabilizer
Arun K. Ghosh,*,† Xiaoming Xu,† Jae-Hun Kim,‡ and Chun-Xiao Xu†
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907, and UniVersity of Illinois at Chicago,
Department of Chemistry, Chicago, Illinois 60607
akghosh@purdue.edu
Received December 22, 2007
ABSTRACT
An enantioselective total synthesis of (
+)-peloruside A (1) is described. Peloruside A (1) is a potent microtubule stabilizer with significant
clinical potential. The synthesis is convergent and involves the assembly of C1
−
C10 segment 2 and C11 C24 segment 3 by a novel aldol
−
protocol followed by Yamaguchi macrolactonization of the resulting seco-acid, selective methylation of hemi-ketal and removal of the protecting
groups to peloruside A.
Peloruside A (1), a 16-membered macrolide antitumor agent,
was first isolated by West and Northcote from the New
Zealand marine sponge, Mycale hentscheli.1 It has shown
potent antitumor activity against P388 murine leukemia cells
with an IC50 value of 10 ng/mL (10 nM). Peloruside A is a
microtubule stabilizing agent and arrests cells in the G2-M
phase.2 However, like laulimalide, it binds to the non-taxoid
site of tubulin and has shown a synergistic effect with taxol.3,4
Peloruside A represents a new class of antitumor agents with
significant clinical potential. The intriguing structure, very
low natural abundance, and clinical potential of peloruside
A has attracted an immense synthetic interest. Thus far, De
Brabander et al. and subsequently Taylor and co-workers
have achieved the total synthesis of peloruside A.5 Further-
more, a number of synthetic studies of peloruside A subunits
have been reported.6 Herein we report a convergent total
synthesis of (+)-peloruside A. The key steps involve efficient
assembly of C1-C10 segment and C11-C24 segment by a
novel reductive enolization followed by a stereoselective
aldol process, an efficient Yamaguchi macrolactonization,
Z-selective olefination, Sharpless asymmetric dihydroxyla-
tion, and Brown’s asymmetric allylation reactions.
As shown in Figure 1, our synthetic strategy involves the
assembly of fragments 2 and 3 by a stereoselective aldol
reaction, followed by a macrolactonization of the corre-
(5) (a) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed.
2003, 42, 1648. (b) Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303.
(6) (a) Paterson, I.; Di Francesco, M. E.; Kuhn, T. Org. Lett. 2003, 5,
599. (b) Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 3967. (c)
Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 7659. (d) Liu, B.;
Zhou, W. S. Org. Lett. 2004, 6, 71. (e) Owen, R. M.; Roush, W. R. Org.
Lett. 2005, 7, 3941. (f) Chen, Z.-L.; Zhou, W. S. Tetrahedron Lett. 2006,
47, 5289. (g) Roulland, E.; Ermolenko, M. S. Org. Lett. 2005, 7, 2225. (h)
Engers, D. W.; Bassindale, M. J.; Pagenkopf, B. L. Org. Lett. 2004, 6,
663. (i) Gurjar, M. K.; Pedduri, Y.; Ramana, C. V.; Puranik, V. G.; Gonnade,
R. G. Tetrahedron Lett. 2004, 45, 387. (j) Taylor, R. E.; Jin, M. Org. Lett.
2003, 5, 4959.
† Purdue University.
‡ University of Illinois at Chicago.
(1) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem. 2000,
65, 445.
(2) Hood, K. A.; West, L. M.; Rouwe, B.; Northcote, P. T.; Berridge,
M. V.; Wakefield, S. J.; Miller, J. H. Cancer Res. 2002, 62, 3356.
(3) Pryor, D. E.; O’Brate, A.; Bilcer, G.; Diaz, J. F.; Wang, Y.; Wang,
Y.; Kabaki, M.; Jung, M. K.; Andreu, J. M.; Ghosh, A. K.; Giannakakou,
P.; Hamel, E. Biochemistry 2002, 41, 9109.
(4) Gaitanos, T. N.; Buey, R. M.; Diaz, J. F.; Northcote, P. T.; Teesdale-
Spittle, P.; Andreu, J. M.; Miller, J. H. Cancer Res. 2004, 64, 5063.
10.1021/ol703091b CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/05/2008

Scheme 1. Synthesis of Enone 2
Figure 1. Retrosynthetic analysis of peloruside A.
sponding carboxylic acid at C1 and hydroxyl group at C-15.
The presence of gem-dimethyl groups at C-10 makes the
C7-C11 lactol segment of peloruside A sterically quite
hindered. Direct aldol reactions involving a gem-dimethyl
ketone or aldehyde typically result in poor yields and side
reactions. In fact, Zhou and co-workers have carried out the
synthesis of the backbone core of peloruside A by an aldol
reaction involving isopropyl ketone.6d In this context, they
have reported numerous difficulties in direct aldol and
Mukaiyama aldol reactions. Both published peloruside A
syntheses utilized methyl ketone aldol reaction and avoided
this problem.5 We, however, planned to install C-10 gem-
dimethyl and C-11 hydroxyl groups by a reductive enoliza-
tion of enone 2 followed by reaction with aldehyde 3. While
this strategy is appealing, there is little to no precedence of
this type of aldol reaction in the literature. To install the C7
and C8 hydroxyl groups, we planned to utilize the Sharpless
asymmetric dihydroxylation reaction.7 The C5 stereocenter
can be introduced stereoselectively by Brown’s asymmetric
allylation process.8 The C2 and C3 chiral centers are derived
from the known compound 4. Aldehyde 3 could be obtained
from Brown’s asymmetric allylation8 of the corresponding
aldehyde derived from 5. The corresponding antipode was
synthesized by us previously.6c
and triphenylphosphine in THF at 0 °C, and (3) reaction of
the resulting iodide with vinylmagnesium bromide in the
presence of a catalytic amount of CuI in THF at -30 °C.
Acid-catalyzed removal of the isopropylidene group followed
by iodoetherification with iodine in the presence of sodium
bicarbonate in acetonitrile afforded the iodide. The C3
hydroxyl group was methylated with trimethyloxonium
tetrafluoroborate and a proton sponge in CH2Cl2 to afford
7.9 Reductive cleavage of the iodoether with zinc dust and
95% ethanol at 80 °C followed by protection of the alcohol
as a MOM ether provided 8. The terminal olefin was
converted to an aldehyde as described by Jin and co-
workers.10 Subsequent asymmetric allylation8 followed by
TBS protection of the resulting alcohol furnished 10. The
terminal olefin was converted to an aldehyde as described
above, and a Horner-Emmons olefination of the resulting
aldehyde using Ando’s protocol11 furnished the Z-olefin 11
selectively (Z:E, 7:1; 89% in three steps). Sharpless asym-
metric dihydroxylation7 of the pure Z-olefin provided the
diol in excellent yield (97%) and diastereoselectivity (dr 6.3:1
As shown in Scheme 1, the synthesis of C1-C10 segment
2 commenced with the commercially available (-)-2,3-O-
isopropylidene-D-threitol 4. It was converted to isopropyl-
idene derivative 6 in a three-step sequence involving (1)
mono-benzylation of 4 with sodum hydride and PMBCl in
THF, (2) conversion of the alcohol to an iodide with iodine
1
by H NMR analysis). Protection of the diol under acidic
conditions furnished isopropylidene derivative 12 in good
yield (94%). Dibal-H reduction in CH2Cl2 at -78 °C yielded
(7) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(8) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432.
(9) Earle, M.; Fairhurst, R.; Giles, R.; Heaney, H. Synlett 1991, 728.
(10) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(11) Ando, K. J. Org. Chem. 1998, 63, 8411.
1002
Org. Lett., Vol. 10, No. 5, 2008

the corresponding aldehyde. Addition of the Grignard reagent
followed by Dess-Martin oxidation of the resulting alcohol
accomplished the synthesis of the key enone segment 2.
Scheme 3. Aldol Coupling and Macrolactone Synthesis
The synthesis of C11-C24 segment 3 is shown in Scheme
2. Homoallylic alcohol 5 was synthesized utilizing chiral
Scheme 2. Stereoselective Synthesis of Aldehyde 3
imide 13 as described previously.6c The hydroxyl group was
protected as a TES ether. Oxidative cleavage of the terminal
olefin provided the aldehyde which was exposed to asym-
metric allylation8 to furnish the alcohol 15 diastereoselec-
tively (dr 5:1 by 1H NMR analysis). The alcohol was
converted to methyl ether 16 as described above, and
oxidative cleavage of the resulting olefin provided aldehyde
3 in good yield.
group. TPAP oxidation of 18 selectively oxidized the primary
alcohol to an aldehyde, which was oxidized with sodium
chlorite to the carboxylic acid. The resulting acid was
Our subsequent elaboration to aldol coupling reaction and
macrolactone synthesis is shown in Scheme 3. With the
synthesis of enone 2 and aldehyde 3, our synthetic strategy
calls for the assembly of these segments by reductive
enolization of enone 2 followed by aldol addition to aldehyde
3. Thus, reaction of 2 with 1.1 equiv of L-selectride at -78
°C for 10 min provided the corresponding enolate. Reaction
of this enolate with aldehyde 3 at -78 °C for 1 h afforded
the aldol product 17 and its diastereomer as a 4:1 mixture
in 92% isolated yield. The diastereomers were readily
separated by silica gel chromatography. The origin of
stereoselectivity as well as the scope and utility of this aldol
coupling process is currently under active investigation. This
aldol protocol is practical and unprecedented. The efficiency
of this process is significantly improved compared to the
direct aldol reactions with a related ketone enolate and
aldehyde reported by Zhou and co-workers.6d,12 The TES
group of 17 was selectively removed by a reaction with a
catalytic amount of DDQ in aqueous THF at 23 °C.
Subsequent exposure of the resulting PMB ether to an excess
of DDQ in the presence of pH 7 buffer removed the PMB
Scheme 4. Completion of Peloruside A
(12) LDA-induced R-dimethyl ketone aldol coupling gave a 29% yield
and 40% loss of starting material; see ref 6d.
Org. Lett., Vol. 10, No. 5, 2008
1003

subjected to Yamaguchi lactonization13 protocol with 2,4,6-
trichlorobenzoyl chloride in the presence of DMAP to
provide the corresponding macrolactone 19 in good yield.
Completion of peloruside A is shown in Scheme 4.
Macrolactone 19 was converted to synthetic (+)-peloruside
A as follows: deprotection of the TBS and isopropylidene
groups with 1 M aqueous HCl to provide a mixture of ketone
and hemi-ketal. Methylation of the resulting diol with
trimethyloxonium tetrafluoroborate in CH2Cl2 selectively
protected the equatorial hydroxyl group to give methyl ether
20.14 Removal of the benzyl group by transfer hydrogenation
conditions followed by removal of MOM group by exposure
to aqueous 4 N HCl at 23 °C furnished 1. Spectral data (1H
and 13C NMR) of synthetic peloruside A (1, [R]23D +15.1, c
0.1, CH2Cl2) are identical to those reported for the natural
(+)-peloruside A.1
In summary, we have achieved an enantioselective syn-
thesis of (+)-peloruside A. The synthesis featured a very
effective reductive aldol process and an efficient formation
of a 16-membered macrolactone. Other key reactions in-
volved selective methylation, Z-selective olefination, Sharp-
less asymmetric dihydroxylation, and Brown’s asymmetric
allylation reactions. Structural modification and biological
studies are currently in progress.
Acknowledgment. This work was partially supported by
the National Institute of Health.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra for compounds 1-3,
(13) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(14) Removal of isopropylidene group resulted in an equilibrium mixture
of macrocycle and hemi-ketal. 1H NMR shows complex mixture. Final
chromatographic purification was made at the last step, and previous
syntheses followed a similar strategy, see ref 5.
6-12, 14-20. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 10, No. 5, 2008