An outside-in approach to adjacent bistetrahydrofuran annonaceous acetogenins with C2 core symmetry. Total synthesis of asimicin and a C32 analogue

Article abstract of DOI:10.1021/ol061352z

A synthesis of the Annonaceous acetogenin asimicin and a side-chain analogue has been achieved by a highly convergent route in which Grubbs cross-metathesis plays a key role.

Full text of DOI:10.1021/ol061352z

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3557-3560
An Outside-In Approach to Adjacent
Bistetrahydrofuran Annonaceous
Acetogenins with C2 Core Symmetry.
Total Synthesis of Asimicin and a C32
Analogue
James A. Marshall* and Jesse J. Sabatini
Department of Chemistry, P.O. Box 400319, UniVersity of Virginia,
CharlottesVille, Virginia 22904
jam5x@Virginia.edu
Received June 2, 2006
ABSTRACT
A synthesis of the Annonaceous acetogenin asimicin and a side-chain analogue has been achieved by a highly convergent route in which
Grubbs cross-metathesis plays a key role.
Since their initial isolation in 1982, Annonaceous acetogenins
have increasingly gained the attention of synthetic and
medicinal chemists. Now numbering over 350 members, this
family exhibits a broad range of bioactivities as potential
pesticides, antifeedants, and immunosuppressive and anti-
tumor agents.1 As the name implies, acetogenins are derived
biogenetically from acetate. Typical structures consist of an
unbranched chain of 30-32 carbon atoms with a central core
unit of one, two, or three adjacent tetrahydrofuran rings near
the midpoint. One end of the chain is attached to the
2-position of a (S)-4-methylbutenolide, which is thought to
be the biological pharmacophore (Figure 1). Compounds
containing two adjacent tetrahydrofuran rings flanked on each
side by hydroxyl substituents and containing one additional
hydroxyl group on either of the attached chains exhibit the
highest cytotoxicity toward tumor cells, including those
exhibiting multiple drug resistance.2
(1) For recent reviews of Annonaceous acetogenins, see: (a) Alali, F.
Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. (b) Zafra-
Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D.
Phytochemistry 1998, 48, 1087. (c) Cave, A.; Figadere, B.; Laurens, A.;
Cortes D. In Progress in the Chemistry of Organic Natural Products:
Acetogenins from Annonaceae; Hertz, W., Ed.; Springer-Verlag: New York,
1997; Vol. 70, pp 81-288. (d) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.;
Gu, Z.-M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275. (e)
Gu, Z.; Zhao, G.; Oberlies, N. H.; Zeng, L.; McLaughlin, J. L. Phytochem-
istry of Medicinal Plants. In Recent AdVances in Phytochemistry; Arnason,
J. T., Mata, R., Romeo, J. T., Eds.; Plenum Press: New York, London,
1995; Vol. 29, pp 249-310.
The core unit of the adjacent bistetrahydrofuran aceto-
genins contains six oxygenated stereocenters, and much of
(2) Oberlies, N. H.; Chang, C.; McLaughlin, J. L. J. Med. Chem. 1997,
40, 2102.
10.1021/ol061352z CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/06/2006

moiety that links the THF core unit to the butenolide terminus
is the most important factor affecting the activity of these
compounds as inhibitors of tumor cell growth.9 The stere-
ochemistry of the core units was judged relatively unimpor-
tant. Related followup NOE studies by McLaughlin and co-
workers on asimicin, parviflorin, and longimicin B bound
to small unilamellar vesicles verified and extended those
conclusions.10 In the aforementioned three acetogenins, the
spacer chain between the butenolide end group and the
tetrahydrofuran core contains, respectively, 13, 11, and 9
carbons. The length of the spacer chain was shown to
influence the conformation of the membrane-bound aceto-
genin with the shorter 9-carbon chain favoring a U-shaped
conformation and the longer 9- and 11-carbon spacers
favoring a sickle-shaped conformer. This conformational
change results in the repositioning of the active butenolide
pharmacophore within the lipid bilayer. The longer chain
acetogenins were 100 times more active than parviflorin in
the brine shrimp lethality screen.
In the present report, we detail a bidirectional outside-in
hydroxy mesylate cascade cyclization route to a threo,trans,
threo,trans,threo-bistetrahydrofuran core unit which can be
further elaborated by Grubbs cross-metathesis11 to a number
of natural Annonaceous acetogenins and analogues. To
illustrate the approach, we selected asimicin8a and a C32
analogue that differ in the length of the alkyl chain attached
to C24 of the bistetrahydrofuran. The route is highly
convergent and should be well suited to the preparation of
additional side-chain analogues.
The first key intermediate in our synthetic sequence, triene
diester 3, had previously been prepared by Hoye and Ye from
all-trans-1,5,9-cyclododecatriene in three steps (45% yield).4
We prepared this diester from 4-penten-1-ol (1) by sequential
Grubbs dimerization and subsequent Swern-Wittig homolo-
gation in 61% yield as a 5:1 mixture of (E)- and (Z)-
isomers.12 Selective asymmetric dihydroxylation with AD-
mix R13 afforded the crystalline diol 4 in 73% yield along
with recovered triene 3. Bisdihydroxylation of the derived
mesylate 5 with AD-mix â led to a tetrol which, without
Figure 1. Structures for bioactive bistetrahydrofuran Annonaceous
acetogenins with threo,trans,threo,trans,threo core stereochemistry.
the synthetic work on the family has been focused in that
direction. The first successful approach was recorded in 1991
by Hoye and co-workers who employed a two-directional
inside-out epoxide cascade sequence to prepare a core
enantiomer of uvaricin.3 This synthesis was important in
establishing the absolute stereostructure of the natural
product. Subsequently, numerous synthetic approaches to
related core tetrahydrofuran arrays have been reported
including a remarkably efficient improvement on their
bidirectional epoxide cascade by Hoye and Ye.4
Other more recent noteworthy achievements include a
bidirectional oxidative cyclization of bishomoallylic alcohols
leading to 36 stereoisomeric bistetrahydrofuran core units
with appendages suitable for further elaboration to a complete
library of core isomers.5,6 A recent report by Tanaka and
co-workers outlines a stereodivergent approach to multiple
core stereoisomers of bistetrahydrofuran core segments.7
The goal of the present study was to develop a convergent
route to a single-core segment of the threo,trans,threo,trans,
threo stereochemistry, present in asimicin and a number of
other highly cytotoxic natural acetogenins (Figure 1),8 with
a view to prepare various analogues differing in the length
and nature of the pendant side chains. We were motivated
to pursue this line of investigation by a report of Miyoshi
and co-workers who concluded from molecular modeling and
SAR studies that the length and flexibility of the spacer
(8) (a) Rupprecht, J. K.; Chang, C. J.; Cassady, J. M.; McLaughlin, J.
L.; Mikolajczak, K. L.; Weisleder, D. Heterocycles 1986, 24, 1197. (b)
Zhao, G. X.; Miesbauer, L. R.; Smith, D. L.; McLaughlin, J. L. J. Med.
Chem. 1994, 37, 1971. (c) Sahai, M.; Singh, S.; Singh, M.; Gupta, Y. K.;
Akashi, S.; Yuji, R.; Hirayam, K.; Asaki, H.; Araya, H. Chem. Pharm.
Bull. 1994, 42, 1163. (d) Zhao, G.-X.; Chao, J.-F.; Zheng, L.; Rieser, M.
J.; McLaughlin, J. L. Bioorg. Med. Chem. 1996, 4, 25. (e) Ye, Q.; He, K.;
Oberlies, N. H.; Zeng, L.; Shi, G.; Evert, D.; McLaughlin, J. L. J. Med.
Chem. 1996, 39, 1790. (f) Sahai, M.; Singh, S.; Singh, M.; Gupta, Y. K.;
Akashi, S.; Yuji, R.; Hirayam, K.; Asaki, H.; Araya, H. Chem. Pharm.
Bull. 1994, 42, 1163. (g) Gu, Z. M.; Fang, X. P.; Zeng, L.; Wood, K. V.;
McLaughlin, J. L Heterocycles 1993, 36, 2221.
(9) Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.; Iwamura, H.;
McLaughlin, J. L. Biochimica Biophys. Acta 1998, 443.
(3) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T. D.; Zhang,
Z. J. Am. Chem. Soc. 1991, 113, 9369.
(10) Shimada, H.; Grutzner, J. B.; Kozlowski, J. F.; McLaughlin, J. L
Biochemistry 1998, 37, 854.
(11) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
(12) In a preliminary report of this methodology, metathesis of ethyl
(E)-2,6-heptadienoate with the Grubbs I ruthenium catalyst was used to
prepare the triene ester 3 as a ca. 2:1 mixture of (E) and (Z) isomers which
was ultimately converted to the threo,cis,threo,cis,threo-isomer of the
bistetrahydrofuran diene 9. Marshall, J. A.; Sabatini, J. J. Org. Lett. 2005,
7, 4819.
(4) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118, 1801.
(5) Das, S.; Li, S.; Abraham, S.; Chen, Z.; Sinha, S. C. J. Org. Chem.
2005, 70, 5922. Avedission, H.; Sinha, S. C.; Yazbek, A.; Sinha, A.; Neogi,
P.; Sinha, S. C.; Keinan, E. J. Org. Chem. 2000, 65, 6035.
(6) Other recent approaches: Takahashi, S.; Nakata, T. J. Org. Chem.
2002, 67, 5739. Nattrass, G. L.; Diez, E.; McLachlan, M. M.; Dixon, D. J.;
Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 580. Tisley, J. M.; Roush, W.
R. J. Am. Chem. Soc. 2005, 127, 10818.
(7) Maezaki, N.; Kojima, N.; Tominaga, H.; Yanai, M.; Tanaka, T. Org.
Lett. 2003, 5, 1411.
(13) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
3558
Org. Lett., Vol. 8, No. 16, 2006

purification, was converted to the bistetrahydrofuran diol
diester 6 in refluxing pyridine5 with an overall yield of 64%
for the three steps. This intermediate was judged to contain
less than 5% of isomeric impurities on the basis of analysis
ether 12 and removal of the alkynyl TMS substituent afforded
the alkyne 13 which, after lithiation and addition to acet-
aldehyde, yielded the propargylic alcohol 14. Oxidation
followed by Noyori asymmetric transfer hydrogenation with
the (S,S) catalyst17 gave the propargylic alcohol 16 with
greater than 95% diastereomeric purity. Attempts to effect
a more convergent synthesis of alcohol 16 through addition
of the lithiated TBS or TES ether derivative of (S)-3-butyn-
2-ol to epoxide 10, with or without BF3 promotion, caused
decomposition of the epoxide.18 The conversion of alcohol
16 to the butenolide 18 was conducted along the lines
reported by Hoye for an analogous intermediate.4
1
of the H NMR spectrum. Protection of the diol 6 as the
MOM ether 7, reduction of the diester with LiAlH4 followed
by sequential Dess-Martin oxidation,14 and Wittig homolo-
gation afforded the threo,trans,threo,trans,threo core diene
unit 9 in 61% overall yield (Scheme 1).
Scheme 1
We were now in a position to address desymmetrization
strategies for further elaboration of the diene core unit 9 to
the acetogenin targets asimicin and its C32 analogue. As
diene 9 is a “type II” olefin, we felt that oligomerization
would defeat attempts at selective mono cross-metathesis
with the butenolide segment 18 or a terminal alkene such as
1-decene.11 Accordingly, we prepared the symmetrical cross-
metathesis products, dienes 19a and 19b, by reaction of diene
9 with 1-decene and 1-octene. The alkenes were employed
in excess to minimize oligomerization of the bis-THF diene
9. The bisbutenolide analogue 20 was likewise prepared from
diene 9 and the butenolide segment 18 (Scheme 3).
Scheme 3
An appropriate 4-hydroxy butenolide side-chain precursor
for our planned synthesis of asimicin and the C32 analogue
was constructed as outlined in Scheme 2 starting from
Scheme 2
Oligomerization of the internal “type III” dienes 19a, 19b,
and 20 was expected to be much slower than a metathesis
exchange with the terminal olefin side-chain precursor 9. In
principle, each of these three internal symmetrical dienes
could provide one of the targeted acetogenins, although the
former two represent the more accessible precursors. The
next stage of our studies was aimed at evaluating the relative
efficiency of the two alternative cross-metathesis strategies.
Reaction of the bisbutenolide 20 with 1 equiv of 1-decene
catalyzed by 5 mol % of Grubbs II catalyst led, after 12 h,
to the asimicin precursor 21a (24%) and recovered bislactone
20 (30%) along with an analyzable but inseparable mixture
of bislactone 23 (21%) and bis-THF diene 19a (6%) and
the monobutenolide 22a (13%) accounting for 94% of the
starting material. With the exception of 23 and 19a, these
products could be easily separated by column chromatog-
raphy on silica gel (Scheme 4).
epoxide 10 prepared by Jacobsen resolution15 of the racemate.
Addition of lithio TMS acetylene led to the alcohol 11 with
>95% enantiomeric purity as measured by 19F NMR analysis
of the Mosher ester.16 Protection of the alcohol as the silyl
(16) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(17) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
(18) Hoye, T. R.; Humpal, P. E.; Jimenez, J. I.; Mayer, M. J.; Tan, L.;
Ye, Z. Tetrahedron Lett. 1994, 35, 7517.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. Meyer, S.
D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(15) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 1360.
Org. Lett., Vol. 8, No. 16, 2006
3559

selectively hydrogenated and the resulting tetrahydro prod-
ucts were subjected to global deprotection with 6 N HCl in
THF-methanol to afford asimicin (22a) and the analogue
22b in high yield (Scheme 6). The spectral properties and
Scheme 4
Scheme 6
rotations of the former were in close agreement with the
reported value. Not surprisingly, the 1H and 13C NMR spectra
of the two were virtually indistinguishable. However, the
high-resolution mass spectra were clearly different and in
full accord with the perceived structures.
The foregoing highly convergent route to Annonaceous
acetogenins with a threo,trans,threo,trans,threo core unit is
straightforward and should be amenable to “mix and match”
variations to access a range of analogues with desirable
medicinal applications. Although the yield of the desired
acetogenin products is less than 50%, the net efficiency of
the process is high because all byproducts can be resubjected
to the metathesis conditions to generate additional quantities
of the final product.19 It should be noted that nearly 100%
of the material is recovered in these reactions.
Cross-metathesis of the bis-THF dienes 19a and 19b with
the butenolide segment 18 proved somewhat more efficient,
affording 38% and 40% of the acetogenin precursors 21a
and 21b and 28% and 19% of recovered starting dienes 19a
and 19b (Scheme 5). The inseparable mixtures of 19a/b and
Scheme 5
Note Added in Proof. Two papers on acetogenin synthesis
appeared after submission of the present manuscript. Both
involve ingenious applications of cross metathesis reactions.
Mucocin: Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org.
Lett. 2006, 8, 2368. Gigantecin: Hoye, T. R.; Eklov, B. M.;
Jeon, J.; Khoroosi, M. Org. Lett. 2006, 8, 3383.
23 could be resubjected to the metathesis procedure leading
to additional quantities of the acetogenin products 21a and
21b.19 The cross products 22a/b could also be recycled with
19a/b to afford the additional asimicin precursor 21a and
its analogue.
Acknowledgment. We thank the UVa College of Arts
and Sciences for partial support of this work.
Supporting Information Available: Experimental pro-
1
To complete the synthesis, the side-chain double bonds
of the principle cross-metathesis products 21a and 21b were
cedures and H NMR spectra for all key compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) A single recycle of the byproducts afforded the asimicin precursor
21a in 25-30% yield.
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