Highly efficient synthesis of the potent antitumor annonaceous acetogenin (+)-parviflorin

Full text of DOI:10.1021/ja953781q

J. Am. Chem. Soc. 1996, 118, 1801-1802
1801
Scheme 1
Highly Efficient Synthesis of the Potent Antitumor
Annonaceous Acetogenin (+)-Parviflorin
Thomas R. Hoye* and Zhixiong Ye
Department of Chemistry, UniVersity of Minnesota
Minneapolis, Minnesota 55455
ReceiVed NoVember 10, 1995
The annonaceous acetogenins are a rapidly growing class of
natural products that have received considerable attention.1
Many members possess a variety of biological effects including
potent cytotoxic, antitumor, and pesticidal activities.2,3 Parvi-
florin (1), a relatively rare C35 adjacent bis-THF acetogenin,
was isolated by McLaughlin et al. both from Asimina parViflora
Duanl.4a and from Annona bullata Rich.4b Parviflorin showed
remarkable selectivity in its cytotoxicity against certain human
solid tumor cell lines.5
The relative configuration of 1 was elucidated from spectral
analysis,4a and the absolute configuration was determined using
Mosher methodology.6 Compound 1 showed spectral data very
similar to those of asimicin (2). They share a threo/trans/threo/
trans/threo configuration at the THF core and a hydroxyl group
at the C(4) position. While five syntheses of bis-THF aceto-
genins or their stereoisomers have been reported,7 we now
describe a synthetic strategy that significantly improves the
overall efficiency for preparation of adjacent bis-THF aceto-
genins. It culminates in a 14-step synthesis of 1.
construction of building block 3 (Scheme 1). Thus, two of the
three double bonds in trans,trans,trans-1,5,9-cyclododecatriene
(4) were selectively oxidized with NMO in the presence of a
catalytic amount of osmium tetraoxide. Oxidative cleavage of
the tetrol with potassium periodate and Wittig extension of the
resultant dialdehyde gave a bis-enoate. This was reduced with
DIBAL-H to provide the first key intermediate, the bis-allylic
alcohol 5, in 51% overall yield from 4.
The stereogenic centers in the bis-THF backbone were
installed by sequential double Sharpless asymmetric epoxidation/
Sharpless asymmetric dihydroxylation, a strategy used by Taber
in the synthesis of (+)-tuberine.8 Thus, epoxidation of 5 with
L-(+)-diethyl tartrate9 gave the diepoxide 6 [∼97% ee after
chromatography; >99% ee (Mosher ester analysis) and 87%
yield after recrystallization]. The primary alcohols were sily-
lated with TBDPSCl. Asymmetric dihydroxylation10 then
afforded an intermediate diol, which was immediately treated
with trifluoroacetic acid to effect an “inside-out” epoxide
cascade reaction producing the bis-THF 7 (85% from 6). Both
carbinol centers in 7 were inverted by sequential treatment with
TsCl and excess TBAF to produce the second key intermediate,
the threo/trans/threo/trans/threo diepoxide 8 (87% from 7).
Selective opening of the diepoxide 8 with lithium (trimethyl-
silyl)acetylide (0.5 molar equiv) in the presence of boron
trifluoride etherate11 provided a mixture of two useful products
incorporating one and two (trimethylsilyl)acetylene units (61%
and 14%, respectively, based upon recovered starting material).
The latter is being used for preparation of C2 symmetric
acetogenin analogs. The former, a desymmetrized bis-THF
monoepoxide, was opened with excess 1-lithio-1-nonyne (89%)
followed by desilylation to give the terminal alkyne 3 (99%).
Vinyl iodide 9 (Scheme 2) was required for coupling with
the terminal alkyne 3. We recently reported a method to
efficiently construct 2-(â-hydroxyalkyl)-4-methylbutenolides.12
Application to acetogenin targets requires a terminal epoxide
with high enantiomeric purity. We now describe an improved
general protocol for preparation of enantiomerically pure 1,2-
epoxy alkanes that also bear a functional group at their remote
terminus. Thus, 1,4-bis(alkenyloxy)benzene 10 (prepared from
Taking advantage of the C2 symmetry within the bis-THF
subunit, we used a bidirectional chain synthesis strategy for the
(1) For reviews, see: (a) Gu, Z.; Zhao, G.; Oberlies, N. H.; Zeng, L.;
McLaughlin, J. L. In Recent AdV. Phytochem.; Arnason, J. T., Mata, R.,
Romeo, J. T., Ed.; Plenum Press: New York, NY, 1995; Vol. 29, Chapter
11. (b) Rupprecht, J. K.; Hui, Y.; McLaughlin, J. L. J. Nat. Prod. 1990,
53, 237. (c) Fang, X.; Rieser, M. J.; Gu, Z.; Zhao, G.; McLaughlin, J. L.
Phytochem. Anal. 1993, 4, 27, 49. (d) Cave, A. Chem. Listy 1993, 87, 24.
(e) Cave, A.; Cortes, D.; Figade`re, B.; Hoequemiller, R.; Laprerote, O.;
Laurens, A.; Leboeuf, M. Recent Phytochem. 1993, 27, 167.
(2) Annonaceous acetogenins interfere with mitochondrial electron
transport processes by interaction with complex I, the multiprotein enzyme,
NADH-ubiquinone reductase.3a-c Selective inhibition of NADH-oxidase in
plasma membrane vesicles isolated from HeLa and HL-60 tumor cells
compared to the oxidase from rat liver cells has recently been suggested to
contribute to the differential cytotoxicities exhibited by bullatacin.3d
(3) (a) Ahammadsahib, K. I.; Hollingworth, R. M.; McGovren, J. P.;
Hui, Y.; McLaughlin J. L. Life Sci. 1993, 53, 1113. (b) Londershausen,
M.; Leicht, W.; Lieb, F.; Moeschler, H.; Weiss, H. Pestic. Sci. 1991, 33,
427. (c) Lewis, M. A.; Arnason, J. T.; Philogene, B. J. R.; Rupprecht, J.
K.; McLaughlin, J. L. Pestic. Biochem. Physiol. 1992, 45, 15. (d) Morre´,
D. J.; de Cabo, R.; Farley, C.; Oberlies, N. H.; McLaughlin, J. L. Life Sci.
1995, 56, 343.
(4) (a) Ratnayake, S.; Gu, Z.; Miesbauer, L. R.; Smith, D. L.; Wood, K.
V.; Evert, D. R.; McLaughlin, J. L. Can. J. Chem. 1994, 72, 287. (b) Gu,
Z.; Fang, X.; Zeng, L.; Wood, K. V.; McLaughlin, J. L. Heterocycles 1993,
36, 2221.
(5) E.g., the ED50s for 1 against human A-549 lung carcinoma, MCF-7
breast carcinoma, and HT-29 colon adenocarcinoma are reported to be 1.27
× 10-15, 1.72, and 0.549 µg/mL, respectively.4b
(8) Taber, D. F.; Bhamidipati, R. S.; Thomas, M. L. J. Org. Chem. 1994,
59, 3442.
(9) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(10) Amberg, W.; Bennani, Y.; Crispino, G. A.; Hartung, J.; Jeong, K.-
S.; Kwong, H.-L.; Morkkawa, K.; Wang, Z.-M.; Xu, D.; Shang, X.-L.;
Sharpless, K. B. J. Org. Chem. 1992, 57, 2768.
(11) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391. (b)
Morris, J.; Wishka, D. G. Tetrahedron Lett. 1986, 27, 803. (c) Mohr, P.;
Tamm, C. Tetrahedron Lett. 1987, 28, 391.
(12) Hoye, T. R.; Humpal, P. E.; Jime´nez, J. I.; Mayer, M. J.; Tan, L.;
Ye, Z. Tetrahedron Lett. 1994, 35, 7517.
(6) Rieser, M. J.; Hui, Y.; Rupprecht, J. K.; Kozlowski, J. F.; Wood, K.
V.; McLaughlin, J. L.; Hanson, P. R.; Zhuang, Z.; Hoye, T. R. J. Am. Chem.
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(7) (a) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T. D.; Zhang,
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0002-7863/96/1518-1801$12.00/0 © 1996 American Chemical Society

1802 J. Am. Chem. Soc., Vol. 118, No. 7, 1996
Communications to the Editor
Scheme 2
Scheme 3
The final Pd0-catalyzed coupling of alkyne 3 with vinyl iodide
97a,b,d gave the enediyne 16 in 82% yield (Scheme 3). Selective
hydrogenation with Wilkinson’s catalyst (71%) left the buteno-
lide intact. Desilylation gave (+)-parviflorin (1, 82%).
In conclusion, the first synthesis of parviflorin (1), a 35-
carbon-containing annonaceous acetogenin, has been achieved.
A highly efficient construction of the adjacent bis-THF backbone
and a new general strategy for preparation of 1,2-epoxides of
high optical purity have been developed. With these very
efficient, convergent strategies it is possible to systematically
design and synthesize various acetogenins and their analogs in
sufficient quantities for the study of structure-activity relation-
ships, biological testing, and prodrug development.
bis-alkylation of hydroquinone with 6-iodo-1-hexene in 72%
yield) was converted to the corresponding tetrol 11 by double
asymmetric dihydroxylation with ∼9:1 facial selectivity at each
alkene using AD-mix-â. Tetrol 11, which has two ω-functional-
1,2-diol units tethered through the hydroquinone linker, was
highly crystalline. Recrystallization from ethyl acetate ef-
ficiently returned material of very high optical purity [>99%
ee (Mosher analysis), 62% yield]. In an efficient one-pot
procedure13 the tetrol 11 was processed into the optically pure
bis-epoxide 12 (92%). Opening of 12 with the lithiated optically
pure 3-butyn-2-ol derivative 13, silylation (TBDPSCl) of the
eventual C(4) hydroxyl group, and selective removal of the TBS
ether produced the propargylic alcohol 14 (68% from 12). The
butenolide 15 was obtained by Red-Al reduction, iodine
treatment, and carbonylation under Stille conditions (81% from
14).12,14 Oxidative release with CAN then afforded a primary
alcohol. Swern oxidation to the corresponding aldehyde and
reaction with chromium(II) chloride and iodoform provided the
terminal vinyl iodide 9 (68% from 15, 5:1 mixture of E/Z
isomers).15
Acknowledgment. This investigation was supported by grants
awarded by the DHHS (GM-34492 and GM-35962) and the American
Cancer Society. We appreciate a beneficial conversation with Professor
D. F. Taber and receipt of a preprint of ref 1a from Professor J. L.
McLaughlin.
Supporting Information Available: Experimental procedures for
preparation and characterization data for all new compounds (39 pages).
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JA953781Q
(15) (a) Takai, K.; Nitta, K.; Ulimoto, K. J. Am. Chem. Soc. 1986, 108,
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(13) Kolb, H.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
(14) Stille, J. K.; Cowell, A. J. Am. Chem. Soc. 1980, 102, 4193.