Synthetic studies of microtubule stabilizing agent peloruside A: An asymmetric synthesis of C10-C24 segment

Article abstract of DOI:10.1016/j.tetlet.2003.08.023

An asymmetric synthesis of the C₁₀-C₂₄ fragment of the potent antitumor macrolide, peloruside A is described. All three stereogenic centers have been enantioselectively constructed utilizing Evans alkylation, Brown asymmetric allylboration, and a substrate controlled epoxide formation. Other key reactions involved Grubbs's ring-closing olefin metathesis and Ando's Z-selective olefination reaction.

Full text of DOI:10.1016/j.tetlet.2003.08.023

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7659–7661
Synthetic studies of microtubule stabilizing agent peloruside A:
an asymmetric synthesis of C10ꢀC24 segment
Arun K. Ghosh* and Jae-Hun Kim
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 3 July 2003; accepted 7 August 2003
Abstract—An asymmetric synthesis of the C10ꢀC24 fragment of the potent antitumor macrolide, peloruside A is described. All
three stereogenic centers have been enantioselectively constructed utilizing Evans alkylation, Brown asymmetric allylboration, and
a substrate controlled epoxide formation. Other key reactions involved Grubbs’s ring-closing olefin metathesis and Ando’s
Z-selective olefination reaction.
© 2003 Elsevier Ltd. All rights reserved.
Peloruside A, a 16-membered macrolide, was recently
isolated from the New Zealand marine sponge Mycale
hentscheli.1 It exhibited potent cytotoxicity against P388
murine leukemia cells with an IC50 value of 10 ng/mL.1
Like paclitaxel, peloruside A has shown microtubule-
stabilizing activity and arrests cells in the G2-M phase.2
It has structural resemblance to epothilones which are
undergoing clinical trials.3 Important antitumor activi-
ties of peloruside A along with its unique structural
features have stimulated immense interest in the synthe-
sis and structure–function studies. Peloruside A’s initial
structure and relative stereochemistry were established
by NMR studies.1 However, its absolute stereochem-
istry was conclusively established only recently after the
first total synthesis4 followed by its chemical and bio-
logical correlation with the natural peloruside A. To
date, De Brabander and co-workers have reported the
only total synthesis. Synthetic approaches toward frag-
ments of peloruside A have been reported by Paterson
et al.5 We recently reported an enantioselective synthe-
sis of the C1ꢀC9 segment of peloruside A.6 In continua-
tion of our on-going studies, we now report a
stereocontrolled route to the C10ꢀC24 segment (3) of
peloruside A where all three stereocenters have been
created by asymmetric synthesis.
fragment 3 by a nucleophilic addition of isopropylmag-
nesium halide to the functionalized d-lactone derived
from acrylate ester 4. The corresponding homoallyl
As shown in Figure 1, our convergent synthetic plan for
peloruside A involves the assembly of C1ꢀC9 segment
(2) and C10ꢀC24 (3) by an aldol reaction followed by a
macrolactonization between the C15-hydroxyl group
and the C1-carboxylic acid. We plan to synthesize the
* Corresponding author. E-mail: arunghos@uic.edu
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.023

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A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 44 (2003) 7659–7661
to install an a,b-unsaturated d-lactone with appropriate
stereochemistry and then elaborate the syn-1,3-diol
functionality by a substrate-controlled diastereoselec-
tive epoxidation followed by reductive opening of the
resulting epoxide. For the synthesis of a,b-unsaturated
d-lactone, ester 9 was first reduced by Dibal-H to
deliver the corresponding alcohol. Dess-Martin periodi-
nane oxidation provided the aldehyde which was sub-
jected to the Brown asymmetric allylboration protocol9
with allyldiisopinocampheylborane to afford homoal-
lylic alcohol 10 as the major diastereomer (dr=93:7 by
1H and 13C NMR). Alcohol 10 was obtained in 65%
yield over two steps after silica gel chromatography.
alcohol will be derived from protected alcohol 5 by
oxidation, olefination and subsequent asymmetric allyl-
boration of the resulting aldehyde utilizing Brown’s
protocol. Protected alcohol 5 will be readily available
by Evans’ asymmetric alkylation reaction.7
As depicted in Scheme 1, asymmetric alkylation of
chiral imide 6 was carried out with benzyloxymethyl
chloride using Evans’ protocol7a to provide the alkyl-
ated product 7 as a single isomer in 80% yield (from
benzyloxazolidinone). Reduction of imide 7 by LiBH4
in THF–MeOH at 23°C afforded alcohol 8. Swern
oxidation of 8 and subsequent Horner–Emmons reac-
tion of the resulting aldehyde with sodium enolate of
(o-cresol)2PꢁO(CH3)CHCO2Et as described by Ando8
furnished tri-substituted Z-olefin 9 in 90% yield over
two steps. The Z-selectivity was >99:1 as revealed by
1H and 13C NMR analysis. Our next synthetic plan was
For synthesis of a,b-unsaturated d-lactone, we relied
upon ring-closing olefin metathesis protocol described
in our recent work.10 Reaction of 10 with acryloyl
chloride and triethylamine at 0°C furnished acryloyl
ester 11. Exposure of 11 to a catalytic amount (10
mol%) of first generation commercial Grubb’s catalyst11
in CH2Cl2 at reflux for 12 h provided a,b-unsaturated
d-lactone 12 in 83% yield after one recycle of the
recovered starting material.12 The use of titanium tetra-
isopropoxide as a co-catalyst (40 mol%) significantly
lowered the yield (62%) of d-lactone 12. Reaction with
second generation Grubb’s catalyst did not improve the
overall yield (74%) either. For elaboration of the g-
hydroxy d-lactone with appropriate stereochemistry, d-
lactone 12 was exposed to nucleophilic epoxidation
with alkaline hydrogen peroxide in methanol at 0°C to
furnish the corresponding epoxide in 74% yield as a
single isomer. Treatment of the resulting epoxide with
diphenyldiselenide and sodium borohydride in 2-
propanol afforded exclusively hydroxylactone 13 in
quantitative yield.13 Lactone 13 possesses the required
syn-1,3-diol stereochemistry necessary for peloruside
A synthesis. Protection of alcohol 13 under standard
condition provided TBDPS ether 14 in quantitative
yield.
For conversion of d-lactone 14 to the C10ꢀC24 fragment,
we first attempted direct opening of lactone ring with
isopropylmagnesium chloride. However, reaction of 14
with excess isopropylmagnesium chloride under a vari-
ety of reaction conditions did not provide the desired
ketone. In an alternative approach, d-lactone 14 was
transformed into C10ꢀC24 fragment ketone 16 as follows
(Scheme 2). Reaction of 14 with N,O-dimethylhydroxyl-
amine hydrochloride in the presence of trimethylalu-
minum in CH2Cl2 according to Weinreb procedure14
furnished the corresponding hydroxy Weinreb amide.
Protection of the resulting alcohol as MEM–ether pro-
vided Weinreb amide 15 in 86% yield (from 14). Treat-
ment of 15 with isopropylmagnesium chloride (5 equiv.)
in THF at 23°C for 5 h afforded C10ꢀC24 fragment
ketone 1615 in 61% yield. It turned out that both MEM-
and TBDPS-protecting groups were critical to form 16.
Replacement of the MEM-group with a PMB-group
resulted in substantial b-elimination as well as degrada-
tion of starting material.
Scheme 1. Reagents and conditions: (a) TiCl4, Et3N, CH2Cl2,
PhCH2OCH2Cl, 0°C, 1.5 h; (b) LiBH4, MeOH, THF, 23°C, 1
h (94%); (c) (COCl)2, DMSO, Et3N, CH2Cl2, −60°C, 45 min;
(d) (o-cresol)2PꢁO(CH3)CHCO2Et, NaH, THF, −78 to
−20°C, 2 h (90% over two steps); (e) Dibal-H, CH2Cl2, −78°
to −40°C, 1 h (96%); (f) Dess–Martin periodinane, NaHCO3,
CH2Cl2, 23°C, 1.5 h; (g) CH2ꢁCHCH2B[(+)-Ipc]2, Et2O,
−80°C, 3 h (65% over two steps); (h) CH2ꢁCHCOCl, Et3N,
CH2Cl2, 0°C, 2 h (77%); (i) Cl2(Pcy)2RuꢁCHPh, CH2Cl2,
40°C, 12 h (83%); (i) H2O2, 6N-aq NaOH, MeOH, 1.5 h
i
(74%); (k) NaBH4, PhSeSePh, AcOH, PrOH, 0°C, 30 min
(quant.); (l) TBDPSCl, imidazole, DMAP, DMF, 23°C, 13 h
(quant.).
In summary, a highly stereoselective synthesis of
C10ꢀC24 segment of peloruside A has been accom-

A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 44 (2003) 7659–7661
7661
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starting material overall isolated yield was 83%.
13. (a) Ghosh, A. K.; Lei, H. J. Org. Chem. 2000, 65, 4779;
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Scheme 2. Reagent and conditions: (a) AlMe3, HN(OCH3)-
CH3·HCl, CH2Cl2, 23°C, 2.5 h (93%); (b) MEMCl, DIPEA,
23°C, 9 h (92%); (c) PrMgCl, THF, 23°C, 5 h (61%).
i
plished. The key steps involved an Evans asymmetric
alkylation, Ando’s Z-selective olefination, Brown asym-
metric allylboration, Grubbs’s ring-closing olefin
metathesis, and substrate controlled stereoselective
epoxidation. Work toward the total synthesis of
peloruside A is in progress.
Acknowledgements
15. All new compounds gave satisfactory spectroscopic and
Partial financial support for this work was provided by
the National Institutes of Health.
analytical results. 16: [h]2D0=+87.5 (c 0.4, CHCl3); IR
(thin film) 2932, 1713, 1429, 1039 cm−1 1H NMR (400
;
MHz, CDCl3) l 7.72–7.67 (m, 4H), 7.42–7.26 (m, 11H),
5.06 (d, J=10.3 Hz, 1H), 4.54 (m, 1H), 4.49–4.42 (m,
4H), 4.34 (d, J=6.8 Hz, 1H), 3.57 (m, 1H), 3.43–3.27 (m,
8H), 2.75 (dd, J=16.0, 4.6 Hz, 1H), 2.63(dd, J=6.0, 7.3
Hz, 1H), 2.59–2.52 (m, 2H), 1.95 (m, 1H), 1.56 (m, 1H),
1.46 (m, 1H), 1.42 (d, J=0.9 Hz, 3H), 1.15 (m, 1H),
1.06–1.01 (m, 15H), 0.79 (t, J=7.5 Hz, 3H); 13C NMR
(125 MHz) l 213.2, 139.2, 136.4, 136.3, 135.6, 134.3,
131.5, 130.0, 129.9, 128.7, 127.9, 127.8 (2C), 92.5, 74.2,
73.3, 72.2, 70.5, 68.4, 67.6, 59.4, 46.9, 42.1, 41.1, 39.5,
27.4 (3C), 25.4, 19.7, 18.3, 18.2, 12.1; HRMS (ESI) m/z
calcd for C42H60O6Si (M++Na) 711.4057, found 711.4045.
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