Highly stereoselective and stereodivergent synthesis of four types of THF cores in acetogenins using a C4-chiral building block

Article abstract of DOI:10.1021/ol026393j

(Formula Presented) Four stereoisomers of the THF cores, synthetic intermediates of acetogenins, have been synthesized with high diastereoselectivity by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation

Full text of DOI:10.1021/ol026393j

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2977-2980
Highly Stereoselective and
Stereodivergent Synthesis of Four
Types of THF Cores in Acetogenins
Using a C -Chiral Building Block
4
Naoyoshi Maezaki, Naoto Kojima, Mikito Asai, Hiroaki Tominaga, 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 June 20, 2002
ABSTRACT
Four stereoisomers of the THF cores, synthetic intermediates of acetogenins, have been synthesized with high diastereoselectivity by asymmetric
alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of r-oxyaldehyde with (S)-3-butyne-1,2-diol
derivatives (C -unit) gave good yields of syn and anti adducts with >97:3 dr and 94:6 dr, respectively. These adducts were converted into the
4
four types of THF compounds via one-pot THF formation or via intramolecular Williamson synthesis.
Annonaceous acetogenins are a class of natural products
possessing an oligo-THF structure with diverse stereochem-
istry. The polyketide natural products have attracted much
attention due to their highly potent antitumor activity.1 The
potency of cytotoxicity and the spectrum against effective
cancer cell lines varied depending on the structure of the
THF moiety characterized by one, two, or three THF ring-
(s) with varying stereochemistry. Therefore, a synthetic route
with high selectivity and excellent divergency is required to
discover compounds with promising anticancer activity.
Considerable efforts have been devoted to synthesize such
compounds.2
The strategy is advantageous in terms of economics (same
reagents used) and ease of operation. Figadere and Casir-
aghies independently reported oligo-THF ring construction
based on Lewis acid-promoted C-glycosylation of lactol
derivatives with 2-(trimethylsiloxy)furan.3 Their method is
useful to synthesize varied collections of the oligo-THF cores
but lacks stereoselectivity. Koert constructed an oligo-THF
structure using nucleophilic addition of 3,4-isopropylidene-
dioxybutyl anion to R-oxyaldehydes. Both syn and anti
adducts were synthesized with high diastereoselectivities by
changing the metal species. However, their approach incurred
a problem regarding the yield in the non-chelation-controlled
addition using an organozinc reagent in the presence of Lewis
Reiterative methodology is a powerful tool when the target
molecules contain repeating subunits such as acetogenins.
(2) For 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. Chemtracts: Org. Chem.
1998, 11, 803-827. (d) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 1998,
4175-4200. (e) Figadere, B. Acc. Chem. Res. 1995, 28, 359-365.
(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.
(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) Zeng, L.; Ye, Q.; Oberlies, N.
H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996,
13, 275-306. (d) Zafra-Polo, M. C.; Gonza´lez, M. C.; Estornell, E.; Sahpaz,
S.; Cortes, D. Phytochemistry 1996, 42, 253-271. (e) Rupprecht, J. K.;
Hui, Y.-H.; McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237-278.
10.1021/ol026393j CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/27/2002

acid due to instability of the reagent under the reaction
conditions.4
diol 1 was converted into the R-oxyaldehyde (R)-3 via a
pivalate 2 in 74% overall yield by the usual method (Scheme
We planned a reiterative synthesis of the oligo-THF
segment based on reagent-controlled asymmetric alkynylation
and stereodivergent THF ring formation as outlined in
Scheme 1.
2).
Scheme 2
Scheme 1
As alkyne components, we employed (S)-3-butyne-1,2-
diol dibenzyl ether (S)-4 prepared from D-mannitol (Scheme
3).7 The choice of benzyl ether for diol protection has the
We envisaged a 3-butyne-1,2-diol derivative as a chiral
C4-unit, both enantiomers of which are readily prepared from
the natural product in enantiomerically pure form. The THF
ring would be constructed via asymmetric alkynylation of
R-oxyaldehyde. The terminal primary alcohol in the resulting
THF compound would become a junction with another C4-
unit by oxidation to the aldehyde. Therefore, this synthetic
strategy can be potentially applied even to a synthesis of
oligo-THF compounds. We expected high diastereoselectivity
by the prominent stereodifferentiating ability of the Carreira
protocol,5 and also convenient stereocontrol by changing only
the chiral ligand. One reason we employed alkynylation is
that the unreacted acetylide can be reused even if the reaction
required excess reagent. Such reuse is difficult in the case
of an organometal reagent generated by halogen-metal
exchange reaction. We also planned stereodivergent synthesis
of four stereoisomers of the THF core from two common
precursors by changing the protocol of THF formation.
In this paper, we describe a highly diastereoselective and
stereodivergent synthesis of all four diastereomers of the THF
cores flanked two hydroxy groups, which are versatile
synthetic intermediates for diverse acetogenins.
Scheme 3
advantage of reducing the number of steps since the
deprotection and reduction of the triple bond can take place
simultaneously. Unfortunately, the asymmetric alkynylation
of (R)-3 with the alkyne (S)-4 in the presence of (1R,2S)- or
(1S,2R)-N-methylephedrine (NME), Zn(OTf)2, and Et3N was
sluggish, and only a trace amount of an adduct 5 was
obtained.8 Most of the aldehyde (R)-3 was decomposed
during the long reaction time (Scheme 3).
We assumed that steric bulkiness of the dibenzyl moiety
in the alkyne (S)-4 impeded the reaction. Therefore, we
examined asymmetric alkynylation of (R)-3 with the alkyne
having diol protection with less steric demand such as bis-
acetyl and cyclohexylidene. However, the bis-acetyl com-
pound did not afford the adduct. Although the cyclohexy-
lidene afforded good results in a synthesis of the syn adduct
(93%, >97:3 dr), the yield and selectivity for the anti adduct
The optically pure aldehyde (R)-3 was synthesized starting
from (R)-tetradecane-1,2-diol 1 prepared by kinetic resolution
of racemic 1-tetradecene oxide with Jacobsen’s catalyst.6 The
(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.
(5) (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.
(7) Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D. L.; Cooper,
G. F. J. Org. Chem. 1991, 56, 1083-1088.
(8) From a model study using chiral lactaldehyde TBS ether and the
alkyne (S)-4, we found that a combination of the (R)-aldehyde and (S)-4
provided better yield and selectivity than that of (S)-aldehyde and (S)-4.
(6) (a) Schaus, S. E.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 4876-4877. (b) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen,
E. N. Science 1997, 277, 936-938.
2978
Org. Lett., Vol. 4, No. 17, 2002

were moderate (43%, 85:15 dr). In addition, selective
deacetalyzation in the presence of TBS group was difficult.
Eventually, we found that a benzylidene acetal is the best
protecting group. The diastereomers of benzylidene acetal
7a and 7b were readily prepared by acetal exchange reaction
of 3-butyne-1,2-diol 6 (PhCH(OMe)2, CSA) in good yield
as an approximately 1:1 diastereomeric mixture, which can
be separated by column chromatography (Scheme 4).9
With the syn and anti adducts 8a and 8b, respectively, in
hand, we examined the stereodivergent THF ring formation.
The results of trans-fused THF ring synthesis using 8a are
depicted in Schemes 5 and 6.
Hydrogenation of 8a using 10% Pd-C in EtOAc afforded
a saturated triol, and subsequent selective sulfonylation of
the primary alcohol with 2,4,6-triisopropylbenzenesulfonyl
chloride (TrisCl) furnished the sulfonate 9 in 82% yield in
two steps. Upon treatment of 9 with K2CO3 in MeOH, the
THF ring formation via an epoxide proceeded smoothly in
a one-pot reaction, giving the trans/threo isomer 10a in 70%
yield (pathway a).
Scheme 4
Scheme 5
Table 1 shows the asymmetric alkynylation of the aldehyde
(R)-3 with the alkynes 7a and 7b. As expected, the reaction
Table 1. Asymmetric Alkynylation of (R)-3 with (3S)-7
On the other hand, the trans/erythro isomer 10b was
synthesized via pathway b (Scheme 6). Selective hydrogena-
tion of the triple bond in the presence of Et3N13 followed by
tosylation of the secondary alcohol transformed 8a into a
tosylate 11 in 96% yield in two steps.14 Then, reductive
deacetalyzation and subsequent intramolecular Williamson
reaction using NaH in THF underwent THF ring formation
rather than THP ring formation to give 10b in 78% yield in
two steps.15
entry
alkyne
7a
NME
yield (%)
8a :8ba
1
2
3
4
1R,2S
1R,2S
1R,2S
1S,2R
74
86
96
quant
>97:3
95:5
>97:3
6:94
7b
7a + 7bb
7a + 7bb
a Determined by 1H NMR spectroscopic data. b Ratio of 7a:7b ) 1.2:1.
Scheme 6
proceeds smoothly to give the adducts in good yield. Both
diastereoisomers provided syn adducts 8a predominantly. The
C1 stereogenic centers in the alkynes 7a and 7b did not show
remarkable effects on either the yield or selectivity (entries
1 and 2). The results indicate that separation of 7a and 7b is
not required in a practical operation. In fact, the syn adduct
8a was obtained in excellent yield with very high diaste-
reoselectivity using a mixture of 7a and 7b (entry 3). We
also found that the anti adduct 8b can be obtained using the
antipode of NME in good yield with acceptable diastereo-
selectivity (entry 4).10 Stereochemistry of the adducts was
assigned by analogy with related compounds.11,12
(12) Signals of the C3′ methine protons in 1H NMR spectral data of the
syn adducts 8a appeared upfield by 0.1-0.2 ppm from those in the anti
adducts 8b. On the other hand, the signals of the OH proton in the syn
adducts appeared downfield by 0.1-0.2 ppm from that in the anti adducts.
The shifts were consistent for each compound in this series.
(13) (a) Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981-13996. (b)
Sajiki, H. Tetrahedron Lett. 1995, 36, 3465-3468.
(9) The stereochemistry of the benzylidene acetal was determined by an
empirical rule (Baggett, N.; Buck, K. W.; Foster, A. B.; Randall, M. H.;
Webber, J. M. J. Chem. Soc. 1965, 3394-3440).
(10) The diastereomeric ratio based on the benzylidene acetal for 8a and
8b was almost same as the ratio of 7a and 7b used.
(11) (a) Clive, D. L. J.; Ardelean, E.-S. J. Org. Chem. 2001, 66, 4841-
4844. (b) Hirama, M.; Shigemoto, T.; Ito, S. J. Org. Chem. 1987, 52, 3342-
3346.
(14) An attempt to obtain 10b via tosylation of 8a followed by
simultaneous reduction of the triple bond and the benzylidene acetal failed
presumably due to hydrogenolysis of the tosyl group.
(15) Koert, U.; Stein, M.; Wagner, H. Chem. Eur. J. 1997, 3, 1170-
1180 and references therein.
Org. Lett., Vol. 4, No. 17, 2002
2979

In a similar manner, a cis/erythro isomer 10c and a cis/
threo isomer 10d were also synthesized from the common
anti adduct 8b in 73 and 57% overall yields, respectively
(Scheme 7).
1
Table 2. Representative H and 13C NMR Spectral Data of
10a-da
Scheme 7
a NMR spectra were recorded in CDCl3 solution at 500 MHz (1H) and
75 MHz (13C).
active acetogenins are under way. These results will be
reported elsewhere.
Representative chemical shifts in 1H and 13C NMR spectral
data of 10a-d are summarized in Table 2. These four
compounds exhibited a characteristic signal pattern, and their
signals are distinguished from each other. Almost no signals
due to other diastereomeric isomers were observed in each
spectral data, thereby indicating the high purity of these
products.
Acknowledgment. We acknowledge financial support by
a Grant-in-Aid for Scientific Research (C) from the Ministry
of Education, Culture, Sports, Science and Technology in
Japan (No. 14572006) and a grant from Shorai Foundation
for Science and Technology. N.K. is grateful to Research
Fellowships of the Japan Society for the Promotion of
Science for Young Scientists.
In conclusion, we have developed a highly stereoselective
and stereodivergent synthesis of four types of the THF cores
in acetogenins. Since the antipodes of all chiral materials
(alkyne, aldehyde, NME) are available, the antipode of each
isomer would be theoretically obtained. Therefore, our
strategy would be applicable to synthesis of various aceto-
genins. Extension of this methodology to synthesis of bis-
and tris-THF cores and synthetic application to biologically
1
Supporting Information Available: H NMR spectra of
compounds 2-4 and 7-11 and experimental procedures for
8a, 8b, 10a, and 10b. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL026393J
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Org. Lett., Vol. 4, No. 17, 2002