Stereoselective synthesis of cis-2,5-disubstituted THFs: Application to adjacent bis-THF cores of annonaceous acetogenins

Article abstract of DOI:10.1021/ol203425p

The iodocyclization of γ,δ-unsaturated alcohols in the presence of a silyl enol ether produced cis-2,5-disubstituted tetrahydrofurans in one pot via siloxy intermediates. N-Iodosuccinimide (NIS) effectively worked as an activator of the double bonds in th

Full text of DOI:10.1021/ol203425p

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1054–1057
Stereoselective Synthesis of cis-2,
5-Disubstituted THFs: Application to
Adjacent Bis-THF Cores of Annonaceous
Acetogenins
Hiromichi Fujioka,* Ryota Maehata, Shintaro Wakamatsu, Kenji Nakahara,
Tatsuya Hayashi, and Tomohiro Oki
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka, 565-0871 Japan
fujioka@phs.osaka-u.ac.jp
Received December 22, 2011
ABSTRACT
The iodocyclization of γ,δ-unsaturated alcohols in the presence of a silyl enol ether produced cis-2,5-disubstituted tetrahydrofurans in one pot via
siloxy intermediates. N-Iodosuccinimide (NIS) effectively worked as an activator of the double bonds in the substrates and the silyl enol ether.
Application to an expedient synthesis of the adjacent bis-tetrahydrofuran core of Annonaceous acetogenins with a cis/threo/cis relative
stereochemistry is also described.
2,5-Disubstituted tetrahydrofurans (THFs) are found in
many biologically active molecules including Annonac-
eous acetogenins,1 polyether antibiotics,2 macrodiolides,3
and others. For the preparation of such valuable skeletons,
several elegant approaches havealready been developed by
many synthetic chemists.4 Among them, the electrophilic
halocyclization of γ,δ-unsaturated alcohols is an attractive
method to construct 2,5-disubstituted THF ring systems
because the starting alcohols are easily prepared5 and the
halogenated product lends itself to further useful synthetic
transformations. In general, the halocyclization of the
γ,δ-unsaturated alcohols favorably produces trans-2,
5-THFs because trans isomers are thermodynamically more
stable than cis isomers.6,7 However, cis-2,5-THF moieties
widely occur in many natural products. In the early 1980s,
Bartlett et al. reported the stereoselective iodocyclization
of benzyloxy derivatives leading to cis-2,5-THFs.7 They
showed that steric repulsion between the protective group
on the hydroxyl function and the substituents at the 2 or 5
positions were critical for the cis-selective fashion. Other
groups also reported synthesis of cis-2,5-THFs based on a
similar strategy,8 although protection of the hydroxyl group
was necessary. The preparation of protected alcohols is
usually conducted under acidic or basic conditions. Aiming
at complex natural product synthesis, the regiocontrolled
(1) (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999,
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62, 504. (b) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269.
(2) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407.
(3) Kang, E. J.; Lee, E. Chem. Rev. 2005, 105, 4348.
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(4) (a) Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry 1993,
4, 1711. (b) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261. (c) Jalce,
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G.; Franck, X.; Figadere, B. Tetrahedron: Asymmetry 2009, 20, 2537.
(7) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
3963.
(5) For the preparation of some γ,δ-unsaturated alcohols, see refer-
ences in the Supporting Information.
(8) (a) Marek, I.; Lefranc-ois, J.-M.; Normant, J.-F. Tetrahedron Lett.
1992, 33, 1747. (b) Zhang, H.; Weifang, S.; Ruan, Z.; Mootoo, D. R.
Tetrahedron Lett. 1995, 36, 649. (c) Ruan, Z.; Dabideen, D.; Blumenstein,
M.; Mootoo, D. R. Tetrahedron 2000, 56, 9203. (d) Kim, S.-W.; Choi,
M.-S.; Park, G.; Kim, Y. S.; Cho, S. G. Bull. Korean Chem. Soc. 2001,
22, 626.
(6) (a) Wiley, A. R.; Harris, T. W.; Brungardt, C.; Marx., M. J. Med.
Chem. 1982, 25, 121. (b) Baldwin, S. W.; McIver, J. M. J. Org. Chem.
1987, 52, 322. (c) Miura, K.; Hondo, T.; Okajima, S.; Hosomi, A.
Tetrahedron Lett. 1996, 37, 487. (d) Harrowven, C. D.; Sibley, E. M. G.
Tetrahedron Lett. 1999, 8299.
r
10.1021/ol203425p
Published on Web 02/08/2012
2012 American Chemical Society

protection of poly hydroxyl compounds is sometimes
problematic. Furthermore, a wide substrate scope has
also not been fully examined to date. In this paper, we
describe a novel diastereoselective iodocylization to give
cis-2,5-THFs from the γ,δ-unsaturated alcohols in a
one-pot procedure using silyl enol ethers for the in situ
silylation.
However, the selectivity was not improved (entry 6). The
TMS group proved to be bulky enough for any steric effect
on the present reaction. Other common solvents for the
halocyclization, such as acetonitrile and THF, gave poor
results (entries 7 and 8).10 N-Bromosuccinimide (NBS) was
not effective for this reaction because the siloxy intermedi-
ate was not formed (entry 9). Compounds 2b and 3b were
formed directly from 1a due to the low reactivity of NBS
toward the silyl enol ether.
With the optimized conditions in hand, we then
explored the generality and scope of the substrates
using various γ,δ-unsaturated alcohols 1 (Table 2). In
entries 1À3, the reaction of alcohols 1bÀd smoothly
proceeded to predominantly give the cis products 2bÀd.
The alcohols with various functional groups 1eÀg were
available for this reaction, and the corresponding prod-
ucts 2eÀg were obtained in high yields without any
difficulty (entries 4À6). It is noteworthy that acid-
labile tert-butyldimethylsilyl (TBS) and triphenyl-
methyl (Tr) groups were not affected under these con-
ditions (entries 5 and 6). Even using the substrates
with internal olefins 1h and 1i, the stereoselective
cyclization proceeded diastereoselectively in high yields
(entries 7 and 8).
For the development of an alternative approach to cis-
2,5-THFs, we proposed that halogenating reagents serve
as an activator of silyl enol ethers to convert the γ,
δ-unsaturated alcohols into the siloxy derivatives and
the successive intramolecular halocyclization, thus yielding
cis-2,5-THFs in one operation.9 We examined the reaction
conditions using 1a as a model substrate to demonstrate
our concept (Table 1). First, the iodocyclization of 1a with
N-iodosuccinimide (NIS) (2.5 equiv) in dichloromethane
produced the trans isomer 3a as a major product, as
expected (entry 1). The iodocyclization in the presence of
varioustypesoftrimethylsilyl(TMS)enolethers4 was next
examined. In entry 2, the addition of 4a resulted in the
reversal of the selectivity, i.e., a 3:1 preference for the cis
isomer 2a. This results indicated that the iodocyclization
occurred via the corresponding silyl ether of 1a. During the
screening of silyl enol ethers (entries 2À5), trimethylsiloxy
cyclohexene 4d gave the best result with a 88% combined
yield and 11:1 selectivity. For enhancement of the selectiv-
ity, more bulky triethylsilyl (TES) derivative 4e was used.
Table 2. Iodocyclization of γ,δ-Unsaturated Alcohol 1a
Table 1. Optimizationa
a Unless otherwise noted, reactions were performed using silyl enol
ether (1.5 equiv) and NIS (2.5 equiv). b Total yields of 2 and 3. c Dr was
determined by 1H NMR. d 1.5 equiv of NIS was used. e NBS was used
instead of NIS.
a Unless otherwise noted, reactions were performed using 4d (1.5
equiv) and NIS (2.5 equiv). b Dr was determined by 1H NMR. c Reac-
tions were performed at À40 °C.
Org. Lett., Vol. 14, No. 4, 2012
1055

In accord with Bartlett’s proposal,7 a plausible explanation
for the reaction mechanism of the present iodocyclization is
exemplified in Scheme 1 using alcohol 1a and silyl enol
ether 4d. Initially, 4d was activated by NIS and reacted
with 1a to give the intermediate 6 and coproduct 5.11 The
minor product 3a should be generated through the high-
energy transition states due to 1,2-steric interactions. As a
result, cis-2,5-THF 2a was favorably obtained.
to bis-THFs with a cis/threo/cis relative stereochemistry
was rather limited.13 We planned the one-pot synthesis of
adjacent bis-THFs using our method. As illustrated in
Scheme 3, the double iodocyclization of C2-symmetric diol
8, which is readily obtained from trans-1,5,9-decatriene by
the regioselective Sharpless asymmetric dihydroxylation,14
produced cis/threo/cis bis-THF 9 in an 83% combined yield
with a 9:1 selectivity.15 In the absence of 4d, the double
iodocyclization favorably produced the trans/threo/trans
isomer.16 These results indicated that the formation of the
newly formed stereogenic centers can be controlled by the
presence or absence of silyl enol ether 4d.
Scheme 1. Plausible Reaction Mechanism
Scheme 3. One-Pot Synthesis of cis/threo/cis Bis-THF 9
Next, the obtained 9 was converted into the cis/threo/cis
bis-THF cores of Annonaceous acetogenins, which are
found in rolliniastatin 1, rollimembrin, and membran-
acin.17 In a previous synthetic route to these natural
products, the stereocenters in bis-THF cores are con-
structedin orderand many reaction steps are required.13cÀf
Although Piccialli reported an elegant one-pot synthesis of
bis-THF rings from linear polyenes by oxidative cycliza-
tion, the product yields were low.13g,h We aimed at the
concise synthesis of Koert and Lee’s common intermediate
1313c,e for the synthesis of the set of natural products,
rolliniastatin 1, rollimembrin, and membranacin (Scheme 4).
The substitutions of two iodine atoms in 9 by sodium
To demonstrate the utility of our products, we per-
formed the substitution of the iodine atom in 2a. Upon
treatments of 2a with sodium azide, sodium thiophenolate
and sodium cyanide, the corresponding substituted com-
pounds 7aÀc were obtained in good yields (Scheme 2).
Scheme 2. Derivatization of 2a
(13) (a) Bruke, S. D.; Jiang, L. Org. Lett. 2001, 3, 1953. (b) Wysocki,
L. M.; Dodge, M. W.; Voight, E. A.; Bruke, S. D. Org. Lett. 2006, 8,
5637. (c) Koert, U. Tetrahedron Lett. 1994, 35, 2517. (d) Head, G. D.;
Whittingham, W. G.; Brown, R. C. D. Synlett 2004, 1437. (e) Keum, G.;
Hwang, C. H.; Kang, S. B.; Kim, Y.; Lee, E. J. Am. Chem. Soc. 2005,
127, 10396. (f) Morris, C. L.; Hu, Y.; Head, G. D.; Brown, L. J.;
Whittingham, W. G.; Brown, R. C. D. J. Org. Chem. 2009, 74, 981.
(g) Bifulco, G.; Caserta, T.; Gomez-Paloma, L.; Piccialli, V. Tetrahedron
Lett. 2002, 43, 9265. (h) Piccialli, V.; Caserta, T.; Caruso, L.; Gomez-
Paloma, L.; Bifulco, G. Tetrahedron 2006, 62, 10989.
Adjacent bis-THF fragments are essential components
of Annonaceous acetogenins, which show a wide array of
biological properties such as antitumor, immunosuppre-
sive, antimicrobial and insecticidal activities.1,12 Although
many methods have been developed for the synthesis of the
bis-THF cores of Annonaceous acetogenins, the approach
(14) Diol 8 was prepared from commercially available trans-1,5,
9-decatriene in one step (57% yield).Tian, S.-K.; Wang, Z.-M.; Jiang,
J.-K.; Shi, M. Tetrahedron: Asymmetry 1999, 10, 2551.
(15) The ratio of two diastereomers was determined by 1H NMR.
Two diasteromers were inseparable and 9 (9:1 dr) was used for further
transformation in Scheme 4.
(16) The iodocyclization of ent-8 with iodine gave trans/threo/trans
bis-THF product as a major isomer with a 7:1 selectivity: Lee, S.; Lee,
Y.-S.; Park, G.; Choi, S.; Yoon, S.-H. Bull. Korean Chem. Soc. 1998, 19,
115.
(17) (a) Pettit, G. R.; Cragg, G. M.; Polonsky, J.; Herald, D. L.;
Goswami, A.; Smith, C. R.; Moretti, C.; Schmidt, J. M.; Weisleder, D.
(9) There are some reports for the iodocyclization of silyl ethers,
though in rather low yields or low selectivity. (a) Reference 7. (b)
Brimble, A. M.; Edmonds, K. M. Tetrahedron 1995, 51, 9995.
(10) Details of optimization are provided in the Supporting
Information.
ꢁ
Can. J. Chem. 1987, 65, 1433. (b) Gonzalez, M. C.; Tormo, J. R.;
Bermejo, A.; Zafra-Polo, M. C.; Estornell, E.; Cortes, D. Bioorg. Med.
(11) We isolated compound 6 and coproduct 5 and confirmed their
structures by 1H NMR (see the Supporting Information).
(12) For a recent review for total synthesis of Annonaceous acet-
ogenins, see: Li, N.; Shi, Z.; Tang, Y.; Chen, J.; Li, X. Beilstein J. Org.
Chem. 2008, 4, 48.
Chem. Lett. 1997, 7, 1113. (c) Saez, J.; Sahpaz, S.; Villaescusa, L.;
ꢁ
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Hocquemiller, R.; Cave, A. J. Nat. Prod. 1993, 56, 351. (d) Chavez,
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D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1999, 62, 1119. (e) Gonzalez,
M. C.; Lavaud, C.; Gallardo, T.; Zafra-Polo, M. C.; Cortes, D. Tetra-
hedron 1998, 54, 6079.
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Org. Lett., Vol. 14, No. 4, 2012

afforded diol 11. The expedient synthesis of compound
13 was achieved via the monoprotection of the hydroxyl
groups and subsequent oxidation of the remained alco-
hol with Dess-Martin periodinane. Consequently, we
accomplished the synthesis of the key intermediate 13
from the known diol 8 in seven steps with a 56% overall
yield.18
Scheme 4. Application to Natural Products Synthesis
In conclusion, we have described the efficient and con-
cise synthesis of cis-2,5-disubstituted THFs from γ,δ-un-
saturated alcohols. Our report is the first example of the
selective synthesis of a cis-2,5-THF stereoisomer from the
alcohol precursors in a one-pot procedure by an iodocy-
clization strategy. The present method is applicable to
various substrates with acid-sensitive functions and inter-
nal olefins. We have achieved the efficient formation of
adjacent bis-THFs with a cis/threo/cis stereochemistry,
which are an essential component of some Annonaceous
acetogenins. We have also disclosed the useful utilization
of a halogenating reagent in organic synthesis.
Acknowledgment. This work was supported by Grant-in-
Aid for Scientific Research from the Japan Society for the
Promotion of Science (JSPS). K.N. acknowledges a
Research Fellowship for Young Scientists from JSPS.
thiophenolate gave 10. Oxidation of thiol, Pummerer
rearrangement of sulfoxide, and reduction of aldehyde
(18) Aldehyde 13 was obtained as an inseparable mixture of two
diastereomers (9:1 dr). The major diastereomer was identical with the
Koert and Lee’s common intermediate 13. The undesired isomer is
separable when the diol 11 is transformed into the corresponding
TBDPS-ether 14 (see the Supporting Information).
Supporting Information Available. Experimental de-
tails and detailed spectroscopic data of all new com-
pounds including TBDPS-ether 14. This material is
available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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