Total synthesis of antitumor depsipeptide (-)-doliculide.

Article abstract of DOI:10.1021/ol0100069

[reaction: see text] (-)-Doliculide, a potent antitumor agent, is synthesized stereoselectively in a convergent manner. The key strategy involves a stereoselective synthesis of the polyketide unit and synthesis of the D-tyrosine derivative, followed by as

Full text of DOI:10.1021/ol0100069

ORGANIC
LETTERS
2001
Vol. 3, No. 4
635-638
Total Synthesis of Antitumor
Depsipeptide (−)-Doliculide
Arun K. Ghosh* and Chunfeng Liu
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received January 12, 2001
ABSTRACT
(−)-Doliculide, a potent antitumor agent, is synthesized stereoselectively in a convergent manner. The key strategy involves a stereoselective
synthesis of the polyketide unit and synthesis of the D-tyrosine derivative, followed by assembly of the fragments by an esterification and
cycloamidation reaction sequence. The synthesis of the polyketide fragment was achieved by an iterative asymmetric synthesis to install
stereoselectively both 1,3-dimethyl groups and the 1,3-diol unit by utilizing asymmetric cyclopropanations and Sharpless asymmetric epoxidations
as the key steps.
(-)-Doliculide (1), a novel 16-membered depsipeptide, has
been recently isolated from the Japanese sea hare Dolabella
auricularia (Aplysiidae).1 Doliculide exhibited exceedingly
potent cytotoxicity against HeLa-S3 cells with an IC50 value
of 1 ng/mL.2 The structure of 1 was initially established by
NMR studies, and its absolute configuration has been
confirmed by a stereoselective total synthesis by Yamada
and co-workers.3 Doliculide possesses a unique 15-carbon
polyketide unit and a substituted D-tyrosine derivative. Apart
from its important biological significance, the unique struc-
tural features and structure-function studies of doliculide
became of interest to us. Herein, we report a convergent and
enantioselective synthesis of (-)-doliculide.
sequence. Our approach to the synthesis of polyketide
fragment 2 involved an iterative asymmetric synthesis to
As depicted in Figure 1, our convergent strategy to 1 relies
upon stereoselective synthesis of the polyketide unit 2,
synthesis of D-tyrosine derivative 3, and its conversion to a
tyrosine-glycine dipeptide, followed by assembly of the
fragment by an esterification and cycloamidation reaction
(1) Ishiwata, H.; Nemoto, T.; Ojika, M.; Yamada, K. J. Org. Chem. 1994,
59, 4710.
(2) Ishiwata, H.; Sone, H.; Kigoshi, H.; Yamada, K. Tetrahedron 1994,
50, 12853.
Figure 1.
(3) Ishiwata, H.; Sone, H.; Kigoshi, H.; Yamada, K. J. Org. Chem. 1994,
59, 4712.
10.1021/ol0100069 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/01/2001

install stereoselectively both 1,3-dimethyl groups and the 1,3-
diol unit. The 1,3-dimethyl groups would be constructed by
iterative Charette asymmetric cyclopropanations4 followed
by opening of the cyclopropane rings, also utilizing Charette’s
protocol.5 Stereoselective elaboration of the 1,3-diol unit
would be achieved by Sharpless asymmetric epoxidations6
followed by regioselective epoxide opening reactions.
Scheme 1a
The synthesis of the polyketide unit 2 began with the
optically active cyanide 4 prepared in multigram quantities
following a previously described procedure.7 Cyanide 4 was
converted to allylic alcohol 5 in a three-step sequence
involving (1) Dibal reduction at 0 °C, (2) Horner-Emmons
olefination of the resulting aldehyde, and (3) Dibal reduction
of the R,â-unsaturated ester to provide the allylic alcohol 5
in 66% yield after chromatography. Charette asymmetric
cyclopropanation of 5 using the amphoteric chiral diox-
aborolane ligand 6 and Zn(CH2I)2‚DME complex provided
the cyclopropane derivative 7 in near quantitative yield and
with high diastereoselectivity (91% de).4 Among a number
of different protocols surveyed for selective opening of the
cyclopropane ring, Charette’s protocol provided the best
results.5 Thus, reaction of 7 with PPh3, imidazole, and iodine
provided the iodide, which upon treatment with n-BuLi at
-78 °C in the presence of TMEDA and molecular sieves
afforded the alkene 8 in 72% yield over two steps.8,9
Hydroboration of alkene 8 with 9-BBN in THF followed by
Swern oxidation of the resulting alcohol provided the
corresponding aldehyde. Following an iterative sequence as
described for 7, the resulting aldehyde was converted to
cyclopropane 9 diastereoselectively. Thus, Horner-Emmons
homologation of the aldehyde, Dibal reduction, and Charette
asymmetric cyclopropanation of the resulting allylic alcohol
with dioxaborolane 6 afforded the cyclopropane 9 in 55%
overall yield from 8.11 Cyclopropane derivative 9 was
converted to olefin 10 in 72% yield by following the same
reaction protocol as 8. Ozonolysis of 10 in CH2Cl2 at -78
°C followed by reductive workup with Ph3P furnished the
corresponding aldehyde. Horner-Emmons olefination fol-
lowed by Dibal reduction of the resulting R,â-unsaturated
ester afforded the allylic alcohol 11 in 59% yield (from 10).
Stereoselective construction of the 1,3-diol unit was achieved
utilizing Sharpless asymmetric epoxidation as the key step.6
As shown in Scheme 2, Sharpless epoxidation of allylic
alcohol 11 was carried out with (-)-DET at -23 °C for 20
h. Epoxide 12 and its diastereomer were isolated as a mixture
a (a) Dibal, CH2Cl2; (b) NaH, (EtO)2P(O)CH2CO2Et, THF, 0 to
23 °C (85-90%); (c) 6 (cat.), Zn(CH2I)2‚DME, CH2Cl2, -15 °C
(99%); (d) I2, PPh3, imidazole, CH2Cl2; (e) n-BuLi, TMEDA, Et2O,
molecular sieves, -78 °C (72%); (f) 9-BBN, THF, H2O2, OH-, 0
°C; (g) Swern oxidation; (h) O3, CH2Cl2, -78 °C, Ph3P.
(5:1) in 90% yield. The presence of the mismatch chirality
is most likely responsible for the somewhat lower observed
diastereoselectivity. The mixture could not be separated and
was used directly for the subsequent transformation. Thus,
Swern oxidation of 12 followed by Wittig homologation of
the resulting aldehyde with the stabilized ylide Ph3Pd
C(CH3)CO2C2H5 in benzene at reflux provided the R,â-
unsaturated ester 13 as an E:Z mixture (96:4) in 81% yield
for two steps. Without separation, the mixture was exposed
to regioselective epoxide opening with HCOOH-NEt3 in
the presence of a catalytic amount (0.06 equiv) of Pd2(dba)3‚
CHCl3 and n-Bu3P to stereoselectively provide the anti
alcohol 14 in 90% yield after chromatography.12 Protection
of the alcohol as a TBDMS ether and then Dibal reduction
followed by Sharpless epoxidation with (+)-DET afforded
epoxy alcohol 15 as a single isomer in 91% yield. Attempts
to directly open the oxirane ring using known procedures
(4) (a) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651.
(b) Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60, 1081
and references therein.
(5) Charette, A. B.; Naud, J. Tetrahedron Lett. 1998, 39, 7259.
(6) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 103-158.
(7) (a) LeBel, N. A.; Banucci, E. G. J. Org. Chem. 1971, 36, 2440. (b)
Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41, 2319.
(8) Ozonalytic cleavage of 8, NaBH4 reduction of the resulting aldehyde,
and formation (BnBr/NaH) of benzyl ether afforded a meso dibenzyl diether.
(9) Hydroboration of 8 and formation of TIPS ether of the resulting
alcohol provided the known10 TIPS ether. Diastereoselectivity of the
cyclopropanation reaction was determined to be 91% de by 13C NMR
analysis.
(10) Hanessian, S.; Murry, P. J. Can. J. Chem. 1984, 64, 2231.
(11) 1H NMR (400 MHz) and 13C NMR (100 MHz) analysis have shown
a 90% de.
(12) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J. J. Am.
Chem. Soc. 1989, 111, 6280.
636
Org. Lett., Vol. 3, No. 4, 2001

Our next synthetic strategy called for the synthesis of Tyr-
Gly dipeptide 19 followed by linking with the polyketide
unit. Commercial D-tyrosine was iodinated with iodine in a
mixture of ethanol and aqueous ammonia as described by
Scheme 2a
Scheme 3a
a (a) Ti(OiPr)4, (-)-DET, t-BuOOH, -23 °C (90%); (b) Swern
oxidation; (c) Ph3PdC(Me)CO2Et, PhH, 84 °C (81%); (d)
Pd2(dba)3‚CHCl3 (cat.), Bu3P, HCO2H, Et3N, Dioxane, 23 °C (90%);
(e) TBSOTf, Et3N, CH2Cl2; (f) DIBAL-H, CH2Cl2, -40 °C (80%);
(g) Ti(OiPr)4, (+)-DET, t-BuOOH, -23 °C (91%); (h) MsCl, Et3N,
DMAP (cat.), CH2Cl2; (i) NaI, butanone, reflux; (j) n-BuLi,
TMEDA, Et2O, -78 °C (84%); (k) H2, 10% Pd-C (cat.), THF
(84%); (l) TPAP (cat.), NMO, CH2Cl2, 23 °C; (m) NaClO2,
methylbutene, t-BuOH-H2O, 23 °C; (n) BOC2O, DMAP (cat.),
t-BuOH, 30 °C (51%).
a (a) TIPSCl, imidazole, DMF, 23 °C (98%); (b) NaH, MeI,
DMF-THF, 60 °C; (c) CF3CO2H, CH2Cl2, 0 to 23 °C; (d) N-BOC-
Gly, EDC, HOBt, DMF, 0 to 23 °C (90%); (e) aq. LiOH, THF, 0
°C; (f) 2, DCC, DMAP, CH2Cl2, -20 °C (98%); (g) BOP, DMAP,
CH2Cl2, 0 to 23 °C (82%); (h) aq. NH3, MeOH, 23 °C (88%); (i)
n-Bu4N+F-, THF, 0 °C, 15 min (98%).
were unsuccessful.13 We then devised an alternative proce-
dure in which 15 was first converted to its iodide by
mesylation and subsequent displacement of the resulting
mesylate with sodium iodide. Treatment of this iodide with
n-BuLi at -78 °C in the presence of TMEDA effected
lithium-iodide exchange followed by epoxide opening to
furnish the allyllic alcohol 16 in 84% overall yield (from
15).1 To complete the synthesis of the polyketide fragment
2, hydrogenation of 16 over 10% Pd-C resulted in deben-
zylation as well as saturation of the olefin. The resulting diol
was transformed into the tert-butyl ester 2 by a three-step
sequence involving (1) selective TPAP oxidation of the
primary alcohol to an aldehyde, (2) NaClO2 oxidation of the
resulting aldehyde, and (3) esterification of the resulting acid
with BOC2O and a catalytic amount of DMAP (51% yield
from 16).
Pitt-Rivers.15 Esterification of the resulting meta-iodo tyrosine
derivative with dry HCl in methanol and BOC protection
provided 17 in 50% overall yield. Protection of the phenolic
group as a TIPS ether followed by N-methylation with
sodium hydride and methyl iodide in a mixture (10:1) of
THF and DMF furnished the N-methylated tyrosine deriva-
tive 18. Removal of the BOC group by treatment with
trifluoroacetic acid and coupling of the resulting amine with
N-BOC-glycine in the presence of EDC and HOBT under
standard conditions afforded the dipeptide 19. Selective
hydrolysis of the methyl ester with LiOH in aqueous THF
at 0 °C for 1 h gave the crude acid, which was subjected to
esterification with polyketide 2 to provide the diester 20 in
98% yield. Treatment of 20 with trifluoroacetic acid effected
deprotection of the TBDMS group, N-BOC, and tert-butyl
ester.
(13) Attempted Cp2TiCl-mediated opening of epoxide 15 resulted in a
trace amount of desired allylic alcohol 16 (<10% yield). For procedure,
see: Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem. Soc. Chem.
Commun. 1990, 8443 and references therein.
(14) For related procedures, see: Burke, S. D.; Buchanan, J. L.; Rovin,
J. D. Tetrahedron Lett. 1991, 32, 3961 and references therein.
(15) Pitt-Rivers, R. Chem. Ind. 1956, 21.
Org. Lett., Vol. 3, No. 4, 2001
637

To effect selective cycloamidation, the resulting amino
acid was reacted with BOP reagent in the presence of DMAP
in CH2Cl2 at 0 to 23 °C for 20 h to afford the desired
cycloamide 21 in 82% yield along with a minor trifluoro-
acetate derivative 22 (10% yield).16 Treatment of 22 with
aqueous ammonia in MeOH at 23 °C for 1 h readily
converted 22 to 21 in 88% yield. Removal of the TIPS ether
in 21 by exposure to n-Bu4N+F- in THF afforded the
synthetic (-)-doliculide 1 {[R]23D -25.4 (c 0.28, MeOH); lit.1
that reported by Yamada and co-workers1 for the natural (-)-
doliculide. Thus, a stereocontrolled synthesis of (-)-doli-
culide has been accomplished. Structure-activity and bio-
logical studies of 1 are the subject of future investigation.
Acknowledgment. Financial support by the National
Institutes of Health (GM 55600) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectral data (1H and 13C NMR) for compounds
1, 2, 4-16, and 19-21. This material is available free of
charge via the Internet at http://pubs.acs.org.
[R]23 -25.5 (c 0.67, MeOH)} in 98% yield. Spectral data
D
(1H and 13C NMR) for synthetic 1 are in full agreement with
(16) The C-7 trifluoacetate derivative was formed during the treatment
of 20 with trifluroacetic acid at 0 to 23 °C.
OL0100069
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