Biomimetic synthesis of the shimalactones

Article abstract of DOI:10.1021/ol702806v

A biomimetic synthesis of shimalactone A and B is described. Its key features are an unprecedented acid-catalyzed cyclization of a dienyl β-ketolactone and a Stille coupling/8π-6π electrocyclization cascade to create the oxabicyclo[2.2.1]heptane and bicyc

Full text of DOI:10.1021/ol702806v

ORGANIC
LETTERS
2
008
Vol. 10, No. 1
49-152
Biomimetic Synthesis of the
Shimalactones
1
Vladimir Sofiyev, Gabriel Navarro, and Dirk Trauner*
Department of Chemistry, UniVersity of California Berkeley,
Berkeley, California 94720-1460
trauner@berkeley.edu
Received November 26, 2007
ABSTRACT
A biomimetic synthesis of shimalactone A and B is described. Its key features are an unprecedented acid-catalyzed cyclization of a dienyl
-ketolactone and a Stille coupling/8 -6 electrocyclization cascade to create the oxabicyclo[2.2.1]heptane and bicyclo[4.2.0]octadiene,
â
π π
respectively. The synthesis is convergent and void of protecting groups.
2
Natural products that arise from 8π-6π electrocyclization
cascades have seen a remarkable surge in recent years. More
than 20 years after the isolation of the endiandric acids,
several pyrone polyketides featuring the bicyclo[4.2.0]-
octadiene retron have been disclosed, occasionally in an
oxidized form (Figure 1). These new natural products,
represented by SNF4435 C, ocellapyrone A, and elysiapyrone
A, have stimulated considerable synthetic activity, which has
led to a deeper understanding of electrocyclization cascades
and polyene chemistry in general.1
stituted double bond. Taken together their two isolated
bicyclic nuclei feature four quaternary stereocenters (two of
them adjacent), which render the shimalactones a consider-
able synthetic challenge.
Biosynthetic considerations add to the attractiveness of the
shimalactones as synthetic targets. In a recent review,1b we
proposed that their biosynthesis could involve heptaenyl
â-ketolactone 1 (Scheme 1). This hypothetical compound is
a fairly regular polyketide that is related to previously isolated
pyrones but has a higher degree of saturation in its
heterocycle.
The shimalactones, a pair of neuritogenic natural products
recently isolated from the cultured marine fungus Emericella
Variecolor, represent an interesting variation of this biosyn-
thetic theme (Figure 1). These fascinating molecules contain
an unprecented oxabicyclo[2.2.1]heptane moiety that is
linked to a bicyclo[4.2.0]octadiene subunit through a trisub-
According to our hypothesis, 1 undergoes enzymatic
epoxidation at the penultimate double bond to afford
intermediate 2. An acid-catalyzed epoxide opening would
then form an undecapentaheptenyl cation 3, which is
eventually converted into its isomeric cation 4 as the positive
charge is carried down the polyene chain. Notably, 3 and 4
are not resonance structures, since the numerous methyl
(
1) (a) For a review of biosynthetic and biomimetic electrocyclizations,
see: Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. ReV. 2005, 105,
757. (b) Miller, A. K.; Trauner, D. Synlett 2006, 14, 2295. (c) For a review
4
(2) (a) Wei, H.; Itoh, T.; Konishita, M.; Kotoku, N.; Kobayashi, M.
Tetrahedron 2005, 61, 8054-8058. (b) Wei, H.; Itoh, T.; Konishita, M.;
Kotoku, N.; Kobayashi, M. Heterocycles 2006, 68, 111-123.
of cascade reactions in synthesis, see: Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134-7186.
1
0.1021/ol702806v CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/12/2007

Scheme 1. Proposed Biosynthesis of Shimalactones
Figure 1. Natural products featuring the bicyclo[4.2.0]octadiene
or -octane) skeleton.
(
substituents on the polyene prevent the π-system from being
3
planar due to A1,3-strain. Once 4 is formed, it is intercepted
by the enol form of the â-keto lactone moiety to form the
oxabicyclo[2.2.1]heptane unit. The resulting conjugated
pentaene moiety has to attain an (E,E,Z,Z,E)-configuration,
which triggers an 8π-6π electrocyclization cascade (via 5
and 6/7). In principle, the electrocyclization cascade could
yield four diastereomeric shimalactones. However, since only
two are found, it appears that the 6π-electrocyclization is
highly diastereoselective, a scenario that has been noted
4
before in the case of the SNF4435 compounds. Of course,
the double-bond isomer of 1 could be involved and the exact
sequence of the electrocyclization cascade and oxabicyclo-
clization cascade to assemble the bicyclo[4.2.0]octadiene unit
of the natural product in a separate and final step.
[2.2.1]heptane formation could be reversed, i.e., the elec-
Accordingly, our synthesis of the shimalactones starts with
a Heathcock anti-aldol addition of the boron enolate of 8 to
iodoenal 9 to afford 10 (Scheme 2), the structure of which
was confirmed by X-ray crystallography (see the Supporting
trocyclization could take place at the stage of an undecap-
entaenyl cation, such as 4.
We now present a total synthesis of the shimalactones that
implements some of the elements of this biosynthetic
proposal. Early in our investigations, however, we determined
that the construction of epoxy hexaene 2 would present a
very difficult synthetic challenge. We therefore decided to
focus on the formation of the oxabicyclo[2.2.1]heptane
moiety first and then use a Stille coupling/8π-6π electrocy-
5,6
Information). Acylation with propionic anhydride gave 11,
which underwent Stille coupling with tributylisopropenyl-
stannane (12) to yield 13. A subsequent Dieckmann cycliza-
tion cleanly afforded â-ketolactone 14 as a single diastere-
7
omer. After careful optimization, we found that treatment
(
5) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. I 1990, 1, 47-
(
3) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E. Org.
Lett. 2005, 7, 2473-2476.
4) Beaudry, C. M.; Trauner, D. Org. Lett. 2005, 7, 4475-4477.
65.
(6) (a) Raimundo, B. C.; Heathcock, C. H. Synlett 1995, 12, 1213-1214.
(
(b) Walker, M.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-5750.
150
Org. Lett., Vol. 10, No. 1, 2008

Scheme 2. Preparation of the Oxabicyclo[2.2.1]heptane
Scheme 3. Total Synthesis of the Shimalactones
could be achieved in high enantiomeric excess using the
1
0
easily available aminophenol 21 as a catalyst. Subsequent
iodine-tin exchange afforded vinyl stannane 23.
With both 19 and 23 in hand, the stage was set for the
final Stille coupling/8π-6π electrocyclization cascade (Scheme
3
). Indeed, this sequence could be achieved under modified
Stille-Liebeskind conditions to afford the shimalactones as
a 5:1 mixture of diastereomers. Whereas the major isomer,
shimalactone A, could be fully purified, shimalactone B was
obtained as a mixture with its diastereomer. All attempts to
separate the two shimalactones further failed. Synthetic
shimalactone A was identical in all respects (NMR, IR, MS,
of 14 with camphorsulfonic acid (CSA) afforded strained
oxabicyclo[2.2.1]heptanes 15a and 15b as a 2:1 mixture of
diastereomers.
[R] ) with the natural product, thus confirming its absolute
D
Our next challenge was the further functionalization of
configuration. Notably, the two other diastereomers that
1
5a. While allylic oxidations failed, radical bromination
could possibly result from the electrocyclization cascade were
not observed. Therefore, the 6π branch of the cascade appears
to be highly diastereoselective, as has been previously
cleanly gave a 1:1 mixture of allylic bromides 16a and 16b.
Oxidation of 16b with IBX yielded unsaturated aldehyde 17,
the structure of which was confirmed by X-ray crystal-
1
a,b
observed in related systems.
8
lography. Although 17 was extremely sensitive toward a
The electrocyclization cascade presumably proceeds through
(E,E,Z,Z,E)-polyene 5, which could never be isolated.
Previous studies by Baldwin and our group have shown that
polyenes of this type undergo facile isomerizations of their
variety of basic conditions, it could be elongated through a
carefully optimized and highly efficient three-step sequence
to afford dienal 18. Stork-Zhao olefination of this aldehyde
then gave the sensitive iodotriene 19.
1
b,11
trisubstituted double bonds.
Therefore, we decided to
A second building block, 23, was assembled through
asymmetric addition of 2-butenyl methyl zinc to the known
iododienal 20 to afford divinylcarbinol 22 (Scheme 3). This
advance compound 16a to the pentaene stage (Scheme 4).
A sequence analogous to the one shown in Scheme 2 gave
iodotriene 24, which underwent cross coupling with stannane
9
(
7) (a) Brand a¨ nge, S.; Leijonmarck, H. Tetrahedron Lett. 1992, 33,
(9) Barbarow, J. E.; Miller, A. K.; Trauner, D. Org. Lett. 2005, 7, 2901-
2903.
(10) Ji, J.; Qiu, L.; Yip, C. W.; Chan, A. S. C. J. Org. Chem. 2003, 68,
1589-1590.
(11) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E.
Tetrahedron 2006, 62, 1675-1689.
3
025-3028. (b) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorenson,
E. J. Org. Lett. 1999, 1, 645-648. (c) Hinterding, K.; Singhanat, S.; Oberer,
L. Tetrahedron Lett. 2001, 42, 8643-8645.
(8) Moorthy, J. N.; Singhal, N.; Senapati, K. Tetrahedron Lett. 2006,
4
7, 1757-1761.
Org. Lett., Vol. 10, No. 1, 2008
151

of a polyenyl â-ketolactone, a reaction that is not possible
in emerocorrugatin A due to the presence of a gem-dimethyl
group.
Scheme 4. An Isolable (Z,E,Z,Z,E)-Pentaene
In summary, we have achieved a convergent and protecting
group-free synthesis of the shimalactones, which supports
our biosynthetic hypothesis on the origin of these compounds.
To this end we have developed a new acid-catalyzed key
cyclization (14f15a,b), which generates two adjacent
quaternary stereocenters in a strained bicyclic ring system.
The scope and limitations of this reaction and its application
to the synthesis of coccidiostatin A are under investigation.
Acknowledgment. This work was supported by National
Institutes of Health Grant R01 GM067636. We thank Dr.
Allen G. Oliver and Dr. Frederick J. Hollander (both from
UC Berkeley) for the crystal structure determination of
compounds 10 and 17.
2
3 to afford (Z,E,Z,Z,E)-pentaene 25. Remarkably, this
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://
pubs.acs.org. Crystallographic data (excluding structure
factors) for compounds 10 and 17 have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. 662079 and 662080. Copies of the data
can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB21EZ, UK (fax: (+44) 1223-
compound was found to resist 8π electrocyclization and
could be isolated. Presumably, the bulk of the oxabicyclo-
[2.2.1]heptaenyl substituent, which would be positioned endo
in an 8π transition state, prevents 25 from undergoing the
cyclization, in stark contrast to its isomer 5. However, despite
repeated attempts, 25 could not be isomerized to the
shimalactones.
While our synthetic studies on the shimalactones were
ongoing, the structures of two new natural products, coc-
cidiostatin A and emecorrugatin A, were reported. Featuring
an oxabicyclo[2.2.1]heptane moiety and a stable (E,Z,Z,Z,Z)-
pentaene, these compounds show some interesting structural
similarities to the shimalactones and stable pentane 25,
3
36-033; e-mail: deposit@ccdc.cam.ac.uk).
OL702806V
(12) Jayasuriya, H.; Guan, Z.; Dombrowski, A. W.; Bills, G. F.;
Polishook, J. D.; Jenkins, R. G.; Koch, L.; Crumley, T.; Tamas, T.; Dubois,
M.; Misura, A.; Darkin-Rattray, S. J.; Gregory, L.; Singh, S. B. J. Nat.
Prod. 2007, 8, 1364-1367.
1
2
respectively. It is conceivable that the biosynthesis of
coccidiostatin A involves an analogous cationic cyclization
152
Org. Lett., Vol. 10, No. 1, 2008