A R T I C L E S
Miller et al.
Chart 1. Selected Guanacastepenes, Heptemerones, and the Neodolastane Skeletona
a Conventional guanacastepene numbering is used on the neodolastane skeleton.
Results and Discussion
reported the total synthesis of racemic guanacastepene C (2) in
2005. In 2006, the asymmetric syntheses of guanacastepene E
(3) and guanacastepene N (4) were completed by Shipe and
Sorensen5x and Overman et al.,5y respectively. In addition to
these completed total syntheses, the groups of Magnus,5z,aa
Lee,4c,5ab,ac Tius,5ad Kwon,5ae,af Srikrishna,5ag Chiu,5ah Brummond,5ai
Stoltz,5aj and Yang5ak,al have published approaches to the
guanacastepenes. Our group has also published approaches
toward a number of guanacastepene architectures.5am-ao We now
report synthetic studies that have culminated in the first total
synthesis of heptemerone B (5) and its conversion into guana-
castepene E (3). For historic and economic reasons, these studies
were conducted in the unnatural enantiomeric series.5ao
Retrosynthetic Analysis. Our retrosynthetic analysis of (-)-
guanacastepene E (3) begins by disconnecting the central seven-
membered ring to arrive at furyl ketone 7 (Scheme 1). In the
forward direction, oxidative coupling of the furan and ketone
functionalities in 7 would close this ring. Further disconnection
of 7 yields the left-hand building block 8 and the right-hand
building block 9. These components would be joined by (formal)
hydrometallation of 8, followed by a diastereoselective conjugate
addition to cyclopentenone 9. Compounds 8 and 9 could be
traced back to iodofuran 10 and dienone 11 through an
intramolecular Heck reaction and ring-closing metathesis (RCM),
respectively. Finally, these components could be fully discon-
nected to known molecules: aldehyde 12, diiodofuran 13,
vinylmagnesium bromide, chiral glyoxylate 14, and heptene 15.
Synthesis of the Left- and Right-Hand Building Blocks.
To reduce this plan to practice, we began to accumulate a
stockpile of known 3,4-diodofuran (13) (Scheme 2). Although
the preparation of this compound from 2-butyne-1,3-diol (16)
according to a published procedure6 proved difficult, our
systematic efforts to improve this transformation were rewarded
with a notable result. When the oxidative cyclization of
diiododiol 17 was run with 1-methyl-2-pyrrolidinone (NMP)
as a cosolvent, we repeatedly observed the formation of large
amounts of a white precipitate lining the reaction vessel. Initially
assuming the precipitate to be an inorganic or polymeric
byproduct, we eventually decided to take a closer look at this
material in order to get a better idea about the mass balance of
the reaction. To our surprise, the white material proved to be
(5) (a) Dudley, G. B.; Danishefsky, S. J. Org. Lett. 2001, 3, 2399-2402. (b)
Dudley, G. B.; Tan, D. S.; Kim, G.; Tanski, J. M.; Danishefsky, S. J.
Tetrahedron Lett. 2001, 42, 6789-6791. (c) Dudley, G. B.; Danishefsky,
S. J.; Sukenick, G. Tetrahedron Lett. 2002, 43, 5605-5606. (d) Tan, D.
S.; Dudley, G. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41,
2185-2188. (e) Lin, S. N.; Dudley, G. B.; Tan, D. S.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2002, 41, 2188-2191. (f) Mandal, M.; Danishefsky,
S. J. Tetrahedron Lett. 2004, 45, 3827-3829. (g) Mandal, M.; Danishefsky,
S. J. Tetrahedron Lett. 2004, 45, 3831-3833. (h) Yun, H. D.; Meng, Z.
Y.; Danishefsky, S. J. Heterocycles 2005, 66, 711-725. (i) Yun, H. D.;
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M.; Yun, H. D.; Dudley, G. B.; Lin, S. N.; Tan, D. S.; Danishefsky, S. J.
J. Org. Chem. 2005, 70, 10619-10637. (k) Cheong, P. H. Y.; Yun, H.;
Danishefsky, S. J.; Houk, K. N. Org. Lett. 2006, 8, 1513-1516. (l) Snider,
B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569-572. (m) Snider, B. B.;
Shi, B. Tetrahedron Lett. 2001, 42, 9123-9126. (n) Shi, B.; Hawryluk, N.
A.; Snider, B. B. J. Org. Chem. 2003, 68, 1030-1042. (o) Boyer, F. D.;
Hanna, I. Tetrahedron Lett. 2002, 43, 7469-7472. (p) Boyer, F. D.; Hanna,
I.; Ricard, L. Org. Lett. 2004, 6, 1817-1820. (q) Boyer, F. D.; Hanna, I.
J. Org. Chem. 2005, 70, 1077-1080. (r) Mehta, G.; Umarye, J. D. Org.
Lett. 2002, 4, 1063-1066. (s) Mehta, G.; Umarye, J. D.; Gagliardini, V.
Tetrahedron Lett. 2002, 43, 6975-6978. (t) Mehta, G.; Umarye, J. D.;
Srinivas, K. Tetrahedron Lett. 2003, 44, 4233-4237. (u) Mehta, G.;
Umarye, J. D. Tetrahedron Lett. 2003, 44, 7285-7289. (v) Mehta, G.;
Pallavi, K.; Umarye, J. D. Chem. Commun. 2005, 4456-4458. (w) Shipe,
W. D.; Sorensen, E. J. Org. Lett. 2002, 4, 2063-2066. (x) Shipe, W. D.;
Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, 7025-7035. (y) Iimura, S.;
Overman, L. E.; Paulini, R.; Zakarian, A. J. Am. Chem. Soc. 2006, 128,
13095-13101. (z) Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V.
Tetrahedron Lett. 2001, 42, 4947-4950. (aa) Magnus, P.; Ollivier, C.
Tetrahedron Lett. 2002, 43, 9605-9609. (ab) Nguyen, T. M.; Lee, D.
Tetrahedron Lett. 2002, 43, 4033-4036. (ac) Nguyen, T. M.; Seifert, R.
J.; Mowrey, D. R.; Lee, D. S. Org. Lett. 2002, 4, 3959-3962. (ad) Nakazaki,
A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363-3366. (ae) Du, X.
H.; Chu, H. F. V.; Kwon, O. Org. Lett. 2003, 5, 1923-1926. (af) Du, X.
H.; Chu, H. F. V.; Kwon, O. Y. Tetrahedron Lett. 2004, 45, 8843-8846.
(ag) Srikrishna, A.; Dethe, D. H. Org. Lett. 2004, 6, 165-168. (ah) Chiu,
P.; Li, S. L. Org. Lett. 2004, 6, 613-616. (ai) Brummond, K. M.; Gao, D.
Org. Lett. 2003, 5, 3491-3494. (aj) Sarpong, R.; Su, J. T.; Stoltz, B. M.
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Deng, L. J.; Liang, S.; Chen, J. H.; Wu, Y. D.; Yang, Z. J. Org. Chem.
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1
highly soluble in chloroform-d, and the H NMR spectrum
revealed an exact 2:1 mixture of NMP and the desired product
13. Thus, the precipitate turned out to be the coordination
polymer 13‚NMP2.
The X-ray structure of 13‚NMP2 reveals the source of its
unusual stability (Figure 1). The carbonyl groups of the amide
moiety in NMP form bonding interactions not only with the
hydrogens in the furan, which are known to act as hydrogen-
bond donors, but also with the iodine atoms. Similar interactions
in iodoalkynes have been studied by Goroff et al.7 Overall, these
bonding interactions lead to the formation of ribbons of
(6) Kraus, G. A.; Wang, X. Synth. Commun. 1998, 28, 1093-1096.
(7) (a) Rege, P. D.; Malkina, O. L.; Goroff, N. S. J. Am. Chem. Soc. 2002,
124, 370-371. (b) Webb, J. A.; Klijn, J. E.; Hill, P. A.; Bennett, J. L.;
Goroff, N. S. J. Org. Chem. 2004, 69, 660-664.
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17058 J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006