Highly functionalized pyranopyrans from furans: A synthesis of the C27-C38 and C44-C53 subunits of norhalichondrin B

Article abstract of DOI:10.1021/ol702559e

(Chemical Equation Presented) A synthesis of highly functionalized pyranopyrans based on an Achmatowicz oxidation followed by a remarkably diastereoselective Kishi reduction is described in the context of studies directed toward norhalichondrin B.

Full text of DOI:10.1021/ol702559e

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5299-5302
Highly Functionalized Pyranopyrans
from Furans: A Synthesis of the
C27−C38 and C44−C53 Subunits of
Norhalichondrin B
James A. Henderson, Katrina L. Jackson, and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado at Boulder,
Boulder, Colorado 80309-0215
andrew.phillips@colorado.edu
Received October 20, 2007
ABSTRACT
A synthesis of highly functionalized pyranopyrans based on an Achmatowicz oxidation followed by a remarkably diastereoselective Kishi
reduction is described in the context of studies directed toward norhalichondrin B.
Since the initial discovery of norhalichondrin A (1, Figure
1) by Uemura and co-workers,1a, and subsequent reports
detailing the structures of related halistatins and halichondrins
from the groups of Uemura,1b Pettit,1c and Blunt and Munro,1d
there has been substantial interest from both chemists and
biologists in this family of compounds.2 Much of the
biological interest is due to their extraordinary in vitro and
in vivo antitumor activities, and the current pinnacle of this
interest is the advancement of Eisai’s halichondrin-derived
E7389, 2, into phase III clinical trials for the treatment of
breast cancer.3
From a chemistry perspective, the halichondrins present
a daunting challenge for chemical synthesis. The structures
are characterized by a 53-55 carbon backbone that is
(1) (a) Uemura, D.; Takahashi, K.; Yamamoto, K.; Yamamoto, T.;
Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chem. Soc. 1985,
107, 4796. (b) Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701. (c)
Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.; Doubek, D. L.; Boyd, M.
R.; Schmidt, J. M.; Chapuis, J. C.; Hamel, E. Bai, R.; Hooper, J. N. A.;
Tackett, L. P. J. Org. Chem. 1993, 58, 2538. (d) Litaudon, M. Hickford, S.
J. H.; Lill, R. E.; Lake, R. J.; Blunt, J. W.; Munro, M. H. G. J. Org. Chem.
1997, 62, 1868.
(2) For a review, see: Hart, J. B.; Lill, R. E.; Hickford, S. J. H.; Blunt,
J. W.; Munro, M. H. G. Drugs Sea 2000, 134-153.
(3) (a) Seletsky, B. M.; Wang, Y.; Hawkins, L. D.; Palme, M. H.;
Figure 1. Norhalichondrin A, halichondrin B, and E7389.
Habgood, G. J.; DiPietro, L. V.; Towle, M. J.; Salvato, K. A.; Wels, B. F.;
Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem.
Lett. 2004, 14, 5547. (b) Yu, M. J.; Kishi, Y.; Littlefield, B. A. In Anticancer
Agents from Natural Products; Cragg, G. M., Kingston, D. G. I., Newman,
decorated by a 2,6,9-trioxatricyclo[3.3.2.03,7] decane, a 22-
D. J., Eds.; CRC Press: Boca Raton, 2005; pp 241-265.
membered macrolactone, and an array of polyoxygenated
10.1021/ol702559e CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/14/2007

pyran and furan rings. To date, only the Kishi group has
been successful in this domain, reporting total syntheses of
halichondrin B, 2, and norhalichondrin B (4, Figure 2) in
containing C27-C38 and C44-C53 domains (5 and 6,
Figure 2) of the norhalichondrins.
An overview of the plans for the synthesis of complex
pyranopyrans 5 and 6 is shown in Figure 2. The genesis of
these two compounds can be traced back to a common
starting material, known furan 7,10 and the overarching
feature in the assembly of these structures is the key role of
the Achmatowicz furan f furanone conversion11 and sub-
sequent Kishi reduction.
The synthesis of the C44-C53 pyranopyran 5 commences
with Brown crotylation of furfural 7 using (-)-(Ipc)2-(E)-
crotylborane to produce 8 in 71% yield (Scheme 1).
Scheme 1
Figure 2. Overview of the synthesis strategy.
1992.4,5 Aside from further illustrating the value of the
Nozaki-Hiyama-Kishi coupling for complex molecule
synthesis, it is noteworthy that the lead compound for the
program that led to E7389 came from the ability to test
materials prepared as part of the Kishi total synthesis.6 A
substantial body of work has also accumulated from the
groups of Burke,7 Horita and Yonemitsu,8 and Salomon.9 In
this paper, we describe our approach to the pyranopyran-
Achmatowicz oxidation of 8 was best performed using the
conditions reported by Ho,12 and upon subjection of 8 to
TBHP in the presence of VO(acac)2 as catalyst, smooth
(4) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S.
H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J.
Am. Chem. Soc. 1992, 114, 3162.
(8) (a) Horita, K.; Hachiya, S.; Nagasawa, M.; Hikota, M.; Yonemitsu,
O. Synlett 1994, 38. (b) Horita, K.; Nagasawa, M.; Hachiya, S.; Yonemitsu,
O. Synlett 1994, 40. (c) Horita, K.; Sakurai, Y.; Nagasawa, M.; Hachiya,
S.; Yonemitsu, O. Synlett 1994, 43. (d) Horita, K.; Sakurai, Y.; Nagasawa,
M.; Maeno, K.; Hachiya, S.; Yonemitsu, O. Synlett 1994, 46. (e) Horita,
K.; Hachiya, S.-i.; Ogihara, K.; Yoshida, Y.; Nagasawa, M.; Yonemitsu,
O. Heterocycles 1996, 42, 99. (f) Horita, K.; Nagasawa, M.; Hachiya, S.-
i.; Sakurai, Y.; Yamazaki, T.; Uenishi, J.; Yonemitsu, O. Tetrahedron Lett.
1997, 38, 8965. (g) Horita, K.; Hachiya, S.-i.; Yamazaki, T.; Naitou, T.;
Uenishi, J.; Yonemitsu, O. Chem. Pharm. Bull. 1997, 45, 1265. (h) Horita,
K.; Sakurai, Y.; Nagasawa, M.; Yonemitsu, O. Chem. Pharm. Bull. 1997,
45, 1558. (i) Yonemitsu, O.; Yamazaki, T.; Uenishi, J.-i. Heterocycles 1998,
49, 89. (j) Horita, K.; Nagasawa, M.; Sakurai, Y.; Yonemitsu, O. Chem.
Pharm. Bull. 1998, 46, 1199. (k) Horita, K.; Nishibe, S.; Yonemitsu, O.
Phytochem. Phytopharm. 2000, 386;
(9) 10. (a) Kim, S.; Salomon, R. G. Tetrahedron Lett. 1989, 30, 6279-
6282. (b) Cooper, A. J.; Salomon, R. G. Tetrahedron Lett. 1990, 31, 3813.
(c) DiFranco, E.; Ravikumar, V. T.; Salomon, R. G. Tetrahedron Lett. 1993,
34, 3247. (d) Cooper, A. J.; Pan, W.; Salomon, R. G. Tetrahedron Lett.
1993, 34, 8193.
(10) Readily obtained on a large scale from â-furylethanol by silylation
with TBSCl (imidazole, DMF, rt) and then DoM (n-BuLi, THF) with DMF
as electrophile. See: Kolb, H. C.; Hoffmann, H. M. R. Tetrahedron 1990,
46, 5127.
(5) For early studies from the Kishi group, see: (a) Aicher, T. D.; Kishi,
Y. Tetrahedron Lett. 1987, 28, 3463. (b) Aicher, T. D.; Buszek, K. R.;
Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Scola, P. M. Tetrahedron
Lett. 1992, 33, 1549. (c) Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung,
S. H.; Kishi, Y.; Scola, P. M.; Yoon, S. K. Tetrahedron Lett. 1992, 33,
1553. (d) Fang, F. G.; Kishi, Y.; Matelich, M. C.; Scola, P. M. Tetrahedron
Lett. 1992, 33, 1557. For recent work, see: Namba, K.; Jun, H.-S.; Kishi,
Y. J. Am. Chem. Soc. 2004, 126, 7770 and references cited therein.
(6) (a) Kishi, Y.; Fang, F. G.; Forsyth, C. J.; Scola, P. M.; Yoon, S. K.
U.S. Patent 5338866, International Patent WO93/17650. (b) See also ref
3b.
(7) (a) Burke, S. D.; Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett.
1991, 32, 3961. (b) Burke, S. D.; Jung, K. W.; Phillips, J. R.; Perri, R. E.
Tetrahedron Lett. 1994, 35, 703. (c) Burke, S. D.; Zhang, G.; Buchanan, J.
L. Tetrahedron Lett. 1995, 36, 7023. (d) Burke, S. D.; Austad, B. C.; Hart,
A. C. J. Org. Chem. 1998, 63, 6770. (e) Burke, S. D.; Quinn, K. J.; Chen,
V. J. J. Org. Chem. 1998, 63, 8626. (f) Burke, S. D.; Jung, K. W.; Lambert,
W. T.; Phillips, J. R.; Klovning, J. J. J. Org. Chem. 2000, 65, 4070. (g)
Austad, B. C.; Hart, A. C.; Burke, S. D. Tetrahedron 2002, 58, 2011. (h)
Jiang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411. (i) Lambert, W. T.; Burke,
S. D. Org. Lett. 2003, 5, 515. (j) Jiang, L.; Martinelli, J. R.; Burke, S. D.
J. Org. Chem. 2003, 68, 1150. (k) Keller, V. A.; Kim, I.; Burke, S. D. Org.
Lett. 2005, 7, 737.
5300
Org. Lett., Vol. 9, No. 25, 2007

Scheme 2
conversion to intermediate pyranone hemiacetal 9 was
Our synthesis of the C27-C38 domain 6 also began with
a Brown crotylation of furfural 7sin this case, use of the
(-)-(Ipc)2-(Z)-crotylborane gave 14 in 75% yield (Scheme
2). Achmatowicz oxidation using VO(acac)2 and tert-butyl
hydroperoxide gave the expected intermediate pyranone 15,
which was immediately subjected to reduction with Et3SiH
in the presence of TFA to produce pyranone 16 in 90% yield
for the two steps. As was the case with the sequence
described above, careful removal of the TBS group with
trifluoroacetic acid in wet CH2Cl2 at -37 °C was followed
by tandem Jones oxidation and heteroconjugate addition of
the acid to the enone to yield pyranolactone 17 (63% overall
from 16). Reduction of the pyranone to the alcohol with
NaBH4 yielded 18 (80%, dr 5:1) and was followed by
reduction of the lactone to the diol with LiBH4 in THF and
subsequent silylation with TBSOTf to produce alkene 19 in
75% yield (two steps). Careful ozonolysis of the olefin to
gave aldehyde 20 (95%), and set the stage for the introduction
of the remaining carbons required for the C27-C38 subunit.
Following Kishi’s lead,5c Nozaki-Hiyama-Kishi reaction
of this aldehyde with methyl trans-3-iodoacrylate gave 21
in 85% yield (dr 2:1).17 Protection of the alcohol as the PMB
ether, removal of TBS ethers, and conversion to the isopro-
pylidene acetal was achieved in 80% yield (21 f 22) by a
three-step sequence consisting of (1) PMBOC(dNH)CCl3,
BF3‚OEt2, (2) HF‚pyridine, and (3) 2,2-dimethoxypropane,
cat. PPTS. Finally, when 22 was treated with TBAF,
heteroconjugate addition proceeded as expected to give the
pyranopyran 6 in 80% yield and in greater than 20:1
diastereoselectivity.
observed. This crude hemiacetal was then immediately
14
treated to Kishi reduction13 with Et3SiH in TFA-CH2Cl2
to produce the desired 2,6-syn-pyranone 10 in 86% yield
over these two steps and with greater than 20:1 diastereo-
selectivity.15 Careful removal of the TBS group with trif-
luoroacetic acid in wet CH2Cl2 at -37 °C was followed by
tandem Jones oxidation and heteroconjugate addition of the
acid to the enone to produce pyranolactone 11 in 63% overall
yield from 10. Installation of the final pyran stereocenter
was achieved by reduction of the ketone with NaBH4 to
produce alcohol 12 (85%, dr ∼ 5:1). Basic hydrolysis of the
lactone, followed by immediate conversion to the methyl
ester with (trimethylsilyl)diazomethane (86%),16 and finally
silylation of the alcohols with TBSOTf, gave pyran 13 (91%;
78% yield from 12). Hydroboration with 9-BBN and
oxidation of the resulting primary alcohol with Dess-Martin
periodinane produced the expected aldehyde (82% over two
steps), completing the synthesis of the targeted pyranone 5.
(11) For reviews of the use of the Achmatowicz reaction in the synthesis
of oxygen-containing heterocycles, see: (a) Georgiadis, M. P.; Albizati,
K. F.; Georgiadis, T. M. Org. Prep. Proced. Int. 1992, 24, 95. (b) Harris,
J. M.; Li, M.; Scott, J. G.; O’Doherty, G. Strategies Tactics Org. Synth.
2004, 5, 221.
(12) Ho, T. -L.; Sapp, S. G. Synth. Commun. 1983, 13, 267.
(13) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976.
(14) For the initial use of TFA in Kishi reductions, see: Kraus, G. A.;
Molina, M. T.; Walling, J. A. J. Chem. Soc., Chem. Commun. 1986, 21,
1568.
(15) To the best of our knowledge, highly diastereoselective reductions
of simple pyranones of this type are without precedent. Studies to elucidate
the underlying source of the remarkable diastereoselectivity of the Kishi
reduction are ongoing and will be reported in due course.
(16) (a) Seyferth, D.; Menzel, H.; Dow, A. W.; Flood, T. C. J. Am. Chem.
Soc. 1968, 90, 1080. (b) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem.
Pharm. Bull. 1981, 29, 1475. (c) For a detailed mechanism, see: Ku¨hnel,
E.; Laffan, D. D. P.; Lloyd-Jones, G. C.; Mart´ınez del Campo, T.;
Shepperson, I. R.; Slaughter, J. L. Angew. Chem., Int. Ed. 2007, 46, 7075.
(17) Recent advancements from the Kishi laboratory include the ability
to perform this reaction in the presence of chiral sulfonamide ligands.
Reported diastereoselectivties for substrates similar to 20 are on the order
of 12:1-15:1. See: Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031.
Org. Lett., Vol. 9, No. 25, 2007
5301

In summary, we have described concise routes to two key
pyranopyran subunits of norhalichondrin B. The synthesis
of the C44-C53 domain 5 proceeds in 12 steps from
commercially available â-furylethanol, and the synthesis of
the C27-C38 domain 6 proceeds in 16 steps from the same
starting material. A key feature of the synthesis is the
application of an Achmatowicz oxidation followed by
oxacarbenium ion reduction for the synthesis of syn-2,6-
substituted pyranones. Efforts toward the integration of this
chemistry into a synthesis of norhalichondrin B are ongoing
and will be reported in due course.
Acknowledgment. We thank Eli Lilly and Company (via
the Lilly Grantee Program), the AP Sloan Foundation, and
the National Cancer Institute (CA 110246) for support of
this research.
Supporting Information Available: Procedures for the
synthesis of all new compounds, along with characterization
data and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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