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.;
ꢁ
ꢁ
Hocquemiller, R.; Cave, A. J. Nat. Prod. 1993, 56, 351. (d) Chavez,
ꢁ
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.
1056
Org. Lett., Vol. 14, No. 4, 2012