An enantioselective synthesis of the C1-C9 segment of antitumor macrolide peloruside A

Article abstract of DOI:10.1016/S0040-4039(03)00744-5

A stereocontrolled synthesis of the C₁-C₉ segment of the marine natural product peloruside A is described. The key steps involve Sharpless's catalytic asymmetric dihydroxylation reaction, a chelation-controlled reduction of chiral β-alkoxy ketones to elaborate the syn-1,3-diol functionality and a ring-closing olefin metathesis of a homoallylic alcohol-derived acrylate ester to form an α,β-unsaturated δ-lactone.

Full text of DOI:10.1016/S0040-4039(03)00744-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3967–3969
An enantioselective synthesis of the C1ꢀC9 segment of antitumor
macrolide peloruside A
Arun K. Ghosh* and Jae-Hun Kim
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 1 February 2003; revised 7 March 2003; accepted 20 March 2003
Abstract—A stereocontrolled synthesis of the C1ꢀC9 segment of the marine natural product peloruside A is described. The key
steps involve Sharpless’s catalytic asymmetric dihydroxylation reaction, a chelation-controlled reduction of chiral b-alkoxy
ketones to elaborate the syn-1,3-diol functionality and a ring-closing olefin metathesis of a homoallylic alcohol-derived acrylate
ester to form an a,b-unsaturated d-lactone. © 2003 Elsevier Science Ltd. All rights reserved.
Macrocyclic marine natural products continue to be a
rich source for potent antitumor agents with unique
structural features.1 However, in many instances
scarcity of natural abundance has hindered subsequent
in-depth biological studies. Peloruside A, a 16-mem-
bered macrolide was recently isolated from the New
Zealand marine sponge Mycale hentscheli.2 It displayed
potent cytotoxicity against P388 murine leukemia cells
at 10 ng/mL. It induces biochemical changes consistent
with apoptosis in a number of cultured mammalian cell
lines.3a More recently, it has been shown that
peloruside A exhibits microtubule-stabilizing activity
and arrests cells in the G2-M phase of the cell cycle
similar to paclitaxel.3b Peloruside A has structural simi-
larity to epothilones which are undergoing clinical tri-
als.4 Peloruside A contains ten stereogenic centers and
its structure and relative stereochemistry have been
elucidated by extensive NMR studies.2 As part of our
continuing interest in the chemistry and biology of
complex natural products with potent antimitotic prop-
erties,5 we became intrigued by the unique structural
features of peloruside A along with its significant anti-
tumor properties. Moreover, scarcity of its supply has
precluded its in-depth biological evaluation. Thus far,
Paterson and co-workers have only reported the synthe-
sis of various fragments of peloruside A.6 Herein, we
describe a convenient enantioselective synthesis of the
C1ꢀC9 segment of peloruside A where all five stereo-
genic centers have been constructed by asymmetric
synthesis.
fragments 2 (C1ꢀC9 segment) and 3 (C10ꢀC24 segment)
by an aldol reaction and subsequent macrolactoniza-
tion between the C1-carboxylic acid and C15-hydroxyl
group. The synthesis of the C1ꢀC9 segment commenced
with the preparation of a,b-unsaturated ester 4 using
known procedures.7 As shown in Scheme 1, ester 4 was
transformed into optically active alcohol 5 by a three-
step sequence involving: (1) Sharpless asymmetric
dihydroxylation8 reaction with AD mix-a in the pres-
ence of methanesulfonamide in a mixture (1:1) of t-
BuOH and H2O at 0°C provided the corresponding diol
in 90% ee;9 (2) exposure of the resulting diol to
dimethoxypropane in the presence of a catalytic
amount of PPTS to form the isopropylidene derivative;
and (3) reduction of the ester with lithium borohydride.
As depicted in Figure 1, our synthetic strategy to
peloruside A is convergent and involves the assembly of
Figure 1.
* Corresponding author. E-mail: arunghos@uic.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00744-5

3968
A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 44 (2003) 3967–3969
stereochemical model 10 in which, due to the presence
of the gem-dimethyl group on the b-face, the carbonyl
reduction proceeded from the less hindered a-face
providing 8 selectively. This three-step sequence is oper-
ationally simple and provided convenient access to
desired alcohol 8. Our next plan was to form an
a,b-unsaturated d-lactone and then elaborate the 1,2-
diol functionality at C7 and C8 stereoselectively. For the
synthesis of the corresponding a,b-unsaturated d-lac-
tone, we utilized the ring-closing olefin metathesis pro-
tocol described by us recently.13 As shown, alcohol 8
was reacted with acryloyl chloride and Et3N in CH2Cl2
at 0°C to afford acrylate ester 11. Acrylate ester 11,
upon exposure to a catalytic amount of first generation
commercial Grubbs’s catalyst14 (10 mol%) in CH2Cl2 at
40°C for 14 h, provided a,b-unsaturated d-lactone 12 in
90% yield after silica gel chromatography.
To append the C7 and C8-1,2-diol functionality, we
attempted catalytic osmylation of a,b-unsaturated d-
lactone 12 in aqueous acetone (Scheme 2). This has
however, provided undesired diol 13 as a single
diastereomer in 67% yield. The depicted stereochem-
istry was assigned based upon NOESY experiments.
Sharpless’s asymmetric dihydroxylation8 of 12 with AD
mix-b did not proceed even after prolonged (24 h)
reaction time at 23°C. This prompted us to investigate
asymmetric dihydroxylation of the corresponding open
chain a,b-unsaturated ester. Thus, saponification of
lactone 12 with aqueous sodium hydroxide was fol-
lowed by protection of the resulting hydroxy acid as the
corresponding TBDMS protected derivative.15 Esterifi-
cation of the resulting acid with diazomethane afforded
Scheme 1. Reagents and conditons: (a) AD mix-a,
CH3SO2NH2, tBuOH–H2O (1:1), 0°C, 36 h, (89%); (b)
Me2C(OMe)2, PPTS (cat.), Me2CO, 23°C, 5 h (92%); (c)
LiBH4, THF, 0°C, 2 h (97%); (d) NaH, BnBr, DMF, 23°C, 4
h (69%); (e) nBu4N+F−, THF, 23°C, 2 h (99%); (f) Dess–Mar-
tin, NaHCO3, CH2Cl2, 23°C, 2 h; (g) CH2ꢁCHCH2B[(−)-
Ipc]2, THF, −78°C, 3 h (71%); (h) CH2ꢁCHCH2MgBr, Et2O,
0°C, 1 h (74%); (i) LiAlH4, LiI, Et2O, −78°C, 30 min (87%);
(j) CH2ꢁCHCOCl, Et3N, CH2Cl2, 0°C, 1 h (62%); (k)
Cl2(PCy3)2RuꢁCHPh, CH2Cl2, 40°C, 14 h (90%).
The overall procedure is very convenient and provided
desired optically active alcohol 5 in 80% yield (three
steps) after silica gel chromatography {[h]2D3=−9.62 (c
0.52, CHCl3)}. Protection of alcohol 5 as a benzyl ether
provided 6 in multigram quantities. Removal of the
TBDPS group followed by Dess–Martin oxidation10 of
the resulting alcohol in CH2Cl2 in the presence of
NaHCO3 for 2 h provided aldehyde 7 in 87% yield.
To install the 1,3-diol functionality selectively, aldehyde
7 was subjected to Brown’s asymmetric allylboration
protocol with allyldiisopinocampheylborane to provide
homoallylic alcohol
8 diastereoselectively in 71%
yield.11 A diastereomeric ratio of 83:17 was determined
1
by H and 13C NMR analysis. In an alternative proce-
dure, aldehyde 7 was also converted to alcohol 8
diastereoselectively using chelation-controlled reduction
as the key step. Thus, treatment of 7 with allylmagne-
sium bromide provided
a diastereomeric mixture
1
(syn:anti=42:58 by H NMR analysis) of alcohols 8
and 9 in 74% yield. The mixture of alcohols 8 and 9
was oxidized by Dess–Martin periodinane10 to give the
corresponding b-ketone in 88% yield. A chelation-con-
trolled reduction by LAH in the presence of LiI at
−78°C in ether provided alcohol 8 diastereoselectively
Scheme 2. Reagents and conditons: (a) OsO4 (cat.), NMO,
Me2CO:H2O (7:1), 23°C, 12 h (72%); (b) NaOH, THF–H2O,
0°C, 14 h; (c) TBDMSCl, imidazole, DMF, 23°C, 18 h; (d)
CH2N2, Et2O, 0°C, 0.5 h (80% for three steps); (e) AD mix-b,
t
CH3SO2NH2, BuOH–H2O (1:1), 0°C, 72 h (72%); (f) nBu4N+
1
(syn:anti=91:9 by H NMR analysis) in 87% yield.12
F−, THF, 23°C, 3 h; (g) Me2C(OMe)2, PPTS (cat.), Me2CO,
23°C, 24 h (63% for two steps).
The observed diastereoselectivity can be rationalized by

A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 44 (2003) 3967–3969
3969
methyl ester 14 in 80% yield over three steps. This
cis-a,b-unsaturated ester was then subjected to asym-
metric dihydroxylation with AD mix-b at 0°C for 72 h.
This afforded a mixture of diastereomeric cis-1,2-diols
in 72% yield with the major product (15) being the
desired diastereomer (diastereomeric ratio 91:9 was
determined by 1H and 13C NMR analysis). The
diastereomers were separated by silica gel chromatogra-
phy. The depicted stereochemistry of 15 and 16 are
based upon subsequent stereochemical assignment of
lactone 17. It should be noted that catalytic osmylation
of 14 at 23°C for 6 h afforded the cis-1,2-diols 15 and
16 as a 1:1 mixture of diastereomers in 85% yield. Diol
15 was converted to d-lactone 17 as follows. Treatment
of 15 with nBu4N+F− in THF resulted in removal of
TBDMS group and concomitant lactonization. Protec-
tion of the diol functionality with dimethoxypropane
and a catalytic amount of PPTS furnished isopropyli-
dene derivative 17 in 63% over two steps.16 Stereochem-
ical assignment of 17 was based upon NOESY
experiments. The spatial proximity of the protons Ha (l
4.24 ppm), Hb (l 4.58 ppm) and Hc (l 4.44 ppm) is
clearly evident in the NOESY spectrum. Either deriva-
tive of 15 or 17 is now suitable for the synthesis of
peloruside A.
4. Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.;
Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods,
C. M. Cancer Res. 1995, 55, 2325.
5. (a) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2002, 122,
11027; (b) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org.
Chem. 2001, 66, 8973; (c) Pryor, D. E.; O’Brate, A.;
Bilcer, G.; Diaz, J. F.; Wang, Y.; Kabaki, M.; Jung, M.
K.; Andreu, J. M.; Ghosh, A. K.; Giannakakou, P.;
Hamel, E. Biochemistry 2002, 41, 9109.
6. Paterson, I.; Di Francesco, M. E.; Kuhn, T. Org. Lett.
2003, 5, 599.
7. Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999,
55, 14013.
8. For an excellent review, please see: Kolb, H. C.; Van-
Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483.
9. Optical purity of the corresponding diol (90% ee) was
determined by chiral HPLC analysis (5% 2-propanol/hex-
ane, flow rate 1 mL/min, Rt=5.3 min for the minor
isomer and Rt=6.8 min for the major isomer) using
Daicel Chiracel OD column.
10. Merger, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59,
7549.
11. (a) Jadhav, P. K.; Bhat, K. S.; Perumaal, T.; Brown, H.
C. J. Org. Chem. 1986, 51, 432; (b) Racgerlaa, U. S.;
Brown, H. C. J. Org. Chem. 1991, 56, 401.
In summary, a stereocontrolled synthesis of the C1ꢀC9
fragment of peloruside A has been achieved. The key
steps are the Sharpless asymmetric dihydroxylation
reaction, Grubbs’ ring-closing olefin metathesis and a
chelation-controlled reduction of a chiral b-alkoxy
ketone to install the syn-1,3-diol functionality stereose-
lectively. Further work toward the total synthesis of
peloruside A is in progress.
12. (a) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67, 8783;
(b) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M.
Tetrahedron Lett. 1988, 29, 5419.
13. (a) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron
Lett. 1998, 39, 4651; (b) Ghosh, A. K.; Liu, C. Chem.
Commun. 1999, 1743; (c) Nicolaou, K. C.; Rodriguez, R.
M.; Mitchell, H. J.; van Delft, F. L. Angew. Chem., Int.
Ed. Engl. 1998, 37, 1874.
14. For an excellent review, see: Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.
15. (a) Ghosh, A. K.; Shin, D.; Mathivanan, P. Chem. Com-
mun. 1999, 1025; (b) Ghosh, A. K.; McKee, S. P.;
Thompson, W. J.; Darke, P. L.; Zugay, J. C. J. Org.
Chem. 1993, 58, 1025.
Acknowledgements
This research work was supported in part by Merck
Research Laboratories and the National Institutes of
Health.
16. All new compounds gave satisfactory spectroscopic and
analytical results. Lactone 17: [h]2D0=+ 43.28 (c 0.67,
1
CHCl3); IR (thin film) 1758 cm−1; H NMR (500 MHz,
CDCl3): l 7.38–7.30 (m, 5H), 4.60–4.51 (m, 3H), 4.44 (m,
1H), 4.24 (d, J=7.7 Hz, 1H), 4.0 (m, 1H), 3.88 (m, 1H),
3.67 (dd, J=9.9, 5 Hz, 1H), 3.54 (dd, J=9.9, 5.7 Hz,
1H), 2.47 (ddd, J=14.2, 8.1, 1.4 Hz, 1H), 2.08 (ddd,
J=14.3, 7.6, 6.2 Hz, 1H), 1.89 (ddd, J=14.3, 6.1, 4.8 Hz,
1H), 1.72 (ddd, J=14.2, 12.1, 8.0), 1.50 (s, 3H), 1.40 (s,
3H), 1.38 (s, 6H); 13C NMR (125 MHz): l 170.6, 138.1,
128.9, 128.3 (2C), 112.1, 109.5, 80.1, 75.3, 74.1, 73.1, 72.9,
72.2, 70.8, 38.6, 34.8, 27.6, 27.3 (2C), 25.7; HRMS (FAB)
m/z calcd for C22H51O7 (M++H): 407.2070; found:
407.2071.
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