Systematic synthesis of bis-THF ring cores in annonaceous acetogenins

Article abstract of DOI:10.1021/ol034131r

(Matrix presented) Systematic synthesis of bis-THF ring cores, synthetic intermediates of adjacent bis-THF annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation

Full text of DOI:10.1021/ol034131r

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1411-1414
Systematic Synthesis of Bis-THF Ring
Cores in Annonaceous Acetogenins
Naoyoshi Maezaki, Naoto Kojima, Hiroaki Tominaga, Minori Yanai, and
Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
Received January 23, 2003
ABSTRACT
Systematic synthesis of bis-THF ring cores, synthetic intermediates of adjacent bis-THF annonaceous acetogenins, has been achieved by
asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of r-tetrahydrofuranic aldehyde
with (S)-3-butyne-1,2-diol derivatives gave good yields of erythro- and threo-adducts with very high diastereoselectivity. These adducts were
converted into four types of bis-THF cores via two kinds of one-pot THF ring formation.
Annonaceous acetogenins are a class of natural products that
have excellent antitumor, pesticidal, antimalarial, immuno-
suppressive, and antifeedant properties (Figure 1).1,2 Over
350 acetogenins have been isolated from various Annonaceae
plants, and they are characterized by the presence of one to
three tetrahydrofuran (THF) rings with various stereochem-
istries in the center of a long hydrocarbon chain that has a
butenolide moiety at the end. In particular, adjacent bis-THF
acetogenins have attracted considerable attention, since they
are biologically the most potent group among all the
acetogenins.
Reiterative methodology is an effective strategy for the
synthesis of acetogenins because they have repeated com-
ponents. Figade`re and Casiraghi developed a unique reitera-
tive procedure based on Lewis acid-promoted C-glycosyda-
tion of lactol derivatives with 2-(trimethylsilyoxy)furan.3
However, their method lacks stereoselectivity. A highly
stereoselective reiterative procedure was developed by Koert
utilizing nucleophilic addition of 3,4-isopropylidenedioxy-
(1) For recent reviews for annonaceous acetogenins, see: (a) Alali, F.
Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. (b)
Zafra-Polo, M. C.; Figade`re, B.; Gallardo, T.; Tormo, J. R.; Cortes, D.
Phytochemistry 1998, 48, 1087-1117. (c) Cave´, A.; Figade´re, B.; Laurens,
A.; Cortes D. In Progress in the Chemistry of Organic Natural Products:
Acetogenins from Annonaceae; Hertz, W., Eds.; 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,
275-306. (e) Zafra-Polo, M. C.; Gonza´lez, M. C.; Estornell, E.; Sahpaz,
S.; Cortes, D. Phytochemistry 1996, 42, 253-271. (f) Gu, Z.-M.; Zhao,
G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin, J. L. In Recent AdVances in
Phytochemistry: ANNONACEOUS ACETOGENINS; Arnason, J. T., Mata,
R., Romeo, J. T., Eds.; Plenum Press: New York, 1995; Vol. 29, pp 249-
310. (g) Fang, X.-P.; Rieser, M. J.; Gu, Z.-M.; Zhao, G.-X.; McLaughlin,
J. L. Phytochem. Anal. 1993, 4, 27-67. (h) Rupprecht, J. K.; Hui, Y.-H.;
McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237-278.
(2) Recent reviews for a synthesis of acetogenins, see: (a) Elliott, M.
C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001, 2303-2340. (b)
Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2000, 1291-1318. (c)
Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G. ChemtractssOrg. Chem.
1998, 11, 803-827. (d) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 1998,
4175-4200. (e) Figade`re, B. Acc. Chem. Res. 1995, 28, 359-365. (f)
Hoppe, R.; Scharf, H.-D. Synthesis 1995, 1447-1464. (g) Koert, U.
Synthesis 1995, 115-132.
Figure 1. Representative structure of annonaceous acetogenins (n
) 1-3, R, R′ ) hydrocarbon chain having oxygenated moities and/
or double bonds).
10.1021/ol034131r CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/03/2003

butyl anion to R-tetrahydrofuranic aldehyde. Although both
erythro- and threo-adducts were obtained with high dia-
stereoselectivities by changing the metal species, their non-
chelation-controlled addition using an organozinc species
gave low yield due to instability of the reagent under the
reaction conditions.4 We have recently developed a highly
stereoselective and stereodivergent synthesis of mono-THF
ring cores using asymmetric alkynylation of 3-butyne-1,2-
diol derivative to R-oxyaldehyde.5 The synthetic strategy is
outlined in Scheme 1. One key step is Carreira’s asymmetric
Next, we examined the asymmetric alkynylation of the
aldehyde 6 with the alkyne 7. In the reagent-controlled
asymmetric alkynylation, it is very important that the reaction
proceeds with high diastereoselectivity not only in the
matched pair but also in the mismatched pair. As mentioned
above, we have achieved the stereodivergent reagent-
controlled asymmetric alkynylation of the R-oxyaldehyde,
wherein high diastereoselectivity was obtained even in the
mismatched pair. In this reaction, the substrates possess one
stereogenic center. It is very important for establishment of
the reiterative procedure that the methodology can be applied
to the substrates with three stereogenic centers. The results
are summarized in Table 1. Fortunately, the coupling reaction
Scheme 1
Table 1. Asymmetric Alkynylation of Tetrahydrofuranic
Aldehyde
alkynylation6 to R-oxyaldehyde (2, m ) 0). This strategy is
potentially applicable to the reiterative construction of an
oligo-THF ring system because the resulting THF ring
compounds (1, m ) 1) can be coupled with the C4-unit after
oxidation of the alcohol to the aldehyde. In this paper, we
describe a highly stereoselective and stereodivergent syn-
thesis of four isomers of the bis-THF ring cores, which are
versatile synthetic intermediates for diverse acetogenins with
potent biological activities. This is the first example of
stereodivergent synthesis of a bis-THF core by reagent-
controlled addition to R-tetrahydrofuranic aldehydes.7
The trans/threo-isomer 5 was selected as the first sub-
strate for bis-THF ring formation since the structure was
frequently found in natural adjacent bis-THF acetogenins,
e.g., asimicin-type and squamocin-I-type acetogenins (Scheme
2).1d R-Tetrahydrofuranic aldehyde 6 was synthesized by
entry
NME
yield (%)
8a /8ba
1
2
1R,2S
1S,2R
97
87
>97:3
3:>97
a Determined by H NMR spectroscopic data.
1
of 6 and 7 using (1R,2S)-N-methylephedrine (NME), Zn(OTf)2,
and Et3N in toluene proceeded smoothly to give the threo-
adduct 8a in good yield with very high diastereoselectivity
(entry 1). We also found that erythro-adduct 8b can be
obtained using the antipode of NME in good yield with high
diastereoselectivity.9 To our knowledge, it is the first example
that the addition to R-tetrahydrofuranic aldehydes was
perfectly controlled by the chiral ligands.
Transformation of the adducts 8a and 8b into the bis-THF
cores was conducted stereodivergently by two kinds of one-
pot THF ring formation.
Scheme 2 a
Scheme 3 shows the trans/threo/trans/threo-bis-THF ring
formation. Hydrogenation of the triple bond accompanied
(5) Maezaki, N.; Kojima, N.; Asai, M.; Tominaga, H.; Tanaka, T. Org.
Lett. 2002, 4, 2977-2980.
a Reagents and conditions: (a) Dess-Martin periodinane, pyri-
dine, CH2Cl2, 0 °C to room temperature, 82%.
(6) (a) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3,
3017-3020. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687-9688. (c) Sasaki, H.; Boyall, D.; Carreira, E. M. HelV. Chim.
Acta 2001, 84, 964-971. (d) Boyall, D.; Lo´pez, F.; Sasaki, H.; Frantz, D.;
Carreira, E. M. Org. Lett. 2000, 2, 4233-4236. (e) Frantz, D. E.; Fa¨ssler,
R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373-381.
(f) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806-1807.
Dess-Martin oxidation8 of the alcohol 5 prepared by our
systematic synthesis of mono-THF ring cores.5
(7) Substrate-controlled nucleophilic addition to R-tetrahydrofuranic
aldehydes was reported; see: (a) Bruns, R.; Kopf, J.; Ko¨ll, P. Chem. Eur.
J. 2000, 6, 1337-1345. (b) Kuriyama, W.; Ishigami, K.; Kitahara, T.
Heterocycles 1999, 50, 981-988. (c) Tian, S.-K.; Wang, Z.-M.; Jiang, J.-
K.; Shi, M. Tetrahedron: Asymmetry 1999, 10, 2551-2562.
(8) Hoppen, S.; Ba¨urle, S.; Koert, U. Chem. Eur. J. 2000, 6, 2382-
2396.
(3) (a) Zanardi, F.; Battistini, L.; Rassu, G.; Pinna, L.; Mor, M.; Culeddu,
N.; Casiraghi, G. J. Org. Chem. 1998, 63, 1368-1369. (b) Figade`re, B.;
Peyrat, J.-F.; Cave´, A. J. Org. Chem. 1997, 62, 3428-3429.
(4) (a) Koert, U. Tetrahedron Lett. 1994, 35, 2517-2520. (b) Koert, U.;
Wagner, H.; Pidun, U. Chem. Ber. 1994, 127, 1447-1457. (c) Koert, U.;
Stein, M.; Harms, K. Tetrahedron Lett. 1993, 34, 2299-2302.
1412
Org. Lett., Vol. 5, No. 9, 2003

the mono-THF ring formation,5 the reductive deacetalization
in EtOAc and the intramolecular Williamson synthesis with
NaH in THF were carried out in a stepwise manner. We
found that the reaction can be performed in a one-pot reaction
with THF as a solvent, giving 12b in good yield without
formation of a THP ring.
Scheme 3 a
In a similar manner, a cis/erythro/trans/threo-isomer 12c
and a cis/threo/trans/threo-isomer 12d were also synthesized
from the common erythro-adduct 8b in 57% and 70% overall
yield, respectively (Scheme 5).
Scheme 5
a Reagents and conditions: (a) H2, 10% Pd-C, EtOAc, room
temperature, 76%; (b) TrisCl, pyridine, CH2Cl2, 0 °C to room
temperature, 71%; (c) K2CO3, MeOH, 0 °C to room temperature,
79%.
by deprotection of the benzylidene acetal in 8a afforded a
saturated triol 9 in 76% yield. Selective sulfonylation of the
primary alcohol with 2,4,6-triisopropylbenzenesulfonyl chlo-
ride (TrisCl) gave the sulfonate 10 in 71% yield. Upon
treatment of 10 with K2CO3 in MeOH, the THF ring
formation via an epoxide 11 proceeded smoothly in a one-
pot reaction to give the trans/threo/trans/threo-bis-THF ring
core 12a in 79% yield (pathway a).10
In conclusion, we have developed a highly stereoselective
systematic synthesis of the bis-THF ring cores in annon-
aceous acetogenins. Asymmetric alkynylation to the aldehyde
with three stereogenic centers proceeded in good yields and
with almost exclusive selectivities. It should be mentioned
that high diastereoselectivity is crucial to obtain the products
with high optical purity, since separation of the diastereo-
isomers is very difficult. Using this methodology, we have
synthesized four diastereoisomers of the bis-THF cores,
including the synthetic intermediate for natural adjacent bis-
THF acetogenins. Moreover, since the antipodes of all chiral
materials (alkyne, aldehyde, NME) are available, this meth-
odology could be applied to synthesize various diastereo-
isomers of the bis-THF cores. Application of our methodol-
ogy to synthesis of biologically active acetogenins is under
way. These results will be reported elsewhere.
On the other hand, the trans/erythro/trans/threo-isomer
12b was obtained via pathway b (Scheme 4). Tosylate 14
Scheme 4 a
Acknowledgment. We acknowledge financial support by
a Grant-in-Aid for Scientific Research (C) from the Japan
(9) The stereochemistry of 8a was determined by comparison of the
chemical shifts around the THF ring in 13C NMR spectroscopic data of
A, which was synthesized from 9 by acetalization and deprotection of the
TBS group, with those of Fujimoto’s synthetic model compounds. In a
similar manner, the stereochemistry of 8b was also determined. Fujimoto,
Y.; Murasaki, C.; Shimada, H.; Nishioka, S.; Kakinuma, K.; Singh, S.;
Singh, M.; Gupta, Y. K.; Sahai, M. Chem. Pharm. Bull. 1994, 42, 1175-
1184.
a Reagents and conditions: (a) H2, 10% Pd-C, Et3N, EtOAc,
room temperature; (b) p-TsCl, pyridine, 0 °C to room temperature,
87% in two steps; (c) H2, 10% Pd-C, THF, room temperature then
NaH, 0 to 40 °C, 77%.
(10) Recently, a one-pot THF ring formation from the 1,2,5-triol
derivatives was reported by Forsyth and co-workers. (a) Dounay, A.
B.; Florence, G. J.; Saito, A.; Forsyth, C. J. Tetrahedron 2002, 58,
1865-1874. (b) Dounay, A. B.; Forsyth, C. J. Org. Lett. 2001, 3, 975-
978.
(11) (a) Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981-13996. (b)
Sajiki, H. Tetrahedron Lett. 1995, 36, 3465-3468.
was obtained in two steps by selective reduction of the triple
bond using Et3N as catalyst poison11 followed by tosylation
of the secondary alcohol. In a previous paper concerning
Org. Lett., Vol. 5, No. 9, 2003
1413

1
Society for the Promotion of Science (No. 14572006) and a
grant from the Shorai Foundation for Science and Tech-
nology. N.K. is grateful for a Research Fellowship of the
Japan Society for the Promotion of Science for Young
Scientists.
Supporting Information Available: H NMR spectra of
compounds 8a,b and 12a-d. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL034131R
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