Progress toward the total synthesis of bacchopetiolone: Application of a tandem aromatic oxidation/Diels-Alder reaction

Article abstract of DOI:10.1021/ol061737h

A stereoselective synthesis of the bacchopetiolone (1) carbocyclic core using a tandem phenolic oxidation/Diels-Alder reaction is described.

Full text of DOI:10.1021/ol061737h

ORGANIC
LETTERS
2
006
Vol. 8, No. 24
421-5424
Progress toward the Total Synthesis of
Bacchopetiolone: Application of a
5
Tandem Aromatic Oxidation/Diels
−Alder
Reaction
Am e´ lie B e´ rub e´ , Ioana Drutu, and John L. Wood*,†
Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 06520-8107
john.l.wood@colostate.edu
Received July 14, 2006
ABSTRACT
A stereoselective synthesis of the bacchopetiolone (1) carbocyclic core using a tandem phenolic oxidation/Diels−Alder reaction is described.
Bacchopetiolone (1) is a dimeric sesquiterpene that was
isolated from a Chilean shrub, Baccaris petiolata, and
reported by Niemeyer and co-workers in 1991. Although
relevance from these studies is the reactivity observed for
3-(2-hydroxyphenyl)-propionic acid 5 (Scheme 2) which,
upon exposure to bis(trifluoroacetoxy)-iodobenzene (BTIB),
produces a polycycle (6) that possesses the same relative
stereochemistry as that found in 1. This stereochemical
outcome indicates that the initially formed spirolactone
undergoes dimerization via approach of the two oxygen-
1
no total synthesis has been reported, the biogenesis of 1 has
been proposed to proceed through a [4+2] cycloaddition of
the bisabolene derivative 2 (Scheme 1). In considering the
proposed biosynthesis of 1, we recognized that synthesis, in
the form of a biomimetic synthetic strategy, could provide
some insight into the dimerization leading to 1. To this end,
we envisioned that a tandem phenolic oxidation/Diels-Alder
reaction of 4 would give rise to 3, an advanced intermediate
which is only two CO units removed from the natural
product.
3
4
bearing faces in an endo transition state.
In addition to 5, we explored the reactivity of 3-(2-
hydroxyphenyl) butyric acid (7), wherein stereogenicity
resides at the benzylic position. Importantly, this substrate
undergoes diastereoselective spirolactonization to furnish 9
which, in the presence of MVK, engages in a stereoelec-
tronically controlled [4+2] reaction (cf., 5 to 6) to furnish 8
as a single diastereomer.
On the basis of the previously observed reactivity of 5
and 7, we speculated that exposure of an appropriately
substituted 3-(2-hydroxyphenyl)-propionic acid (e.g., 4) to
The feasibility of this strategy was supported by recent
studies in our laboratories on the tandem phenolic oxidation/
2
Diels-Alder reactions of aryl propionic acids. Of particular
†
Current Address: Department of Chemistry, Colorado State University,
Fort Collins, CO 80523-1872.
(
1) Zdero, C.; Bohlmann, F.; Niemeyer, H. M. Phytochemistry 1991,
0, 1597-1601.
2) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4, 493-
96.
(3) Hou, H. F.; Peddinti, R. K.; Liao, C. C. Org. Lett. 2002, 4, 2477-
2480.
(4) Gao, S. Y.; Ko, S.; Lin, Y. L.; Peddinti, R. K.; Liao, C. C.
Tetrahedron 2001, 57, 297-308.
3
(
4
1
0.1021/ol061737h CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/28/2006

Scheme 1
Scheme 3
oxidation. To our delight, we found that treatment of 13 with
BTIB resulted in smooth aromatic oxidation followed by
Diels-Alder cycloaddition to provide dimer 3 as a single
BTIB would result in the stereoselective formation of 3
(Scheme 1).
To explore this hypothesis, we initiated a synthetic effort
6
that began with large scale production of bromide 11 from
diastereomer in 60% yield. This short reaction sequence
5
cyclopropylmethyl ketone (10). Subsequent exposure of 11
allowed access to several grams of dimer 3, and single X-ray
analysis provided structural proof that 3 possesses the rela-
tive stereochemistry found in bacchopetiolone (Scheme 3,
inset).
to lithium-halogen exchange followed by copper-mediated
Scheme 2
Having assembled the polycyclic skeleton of bacchopeti-
olone, we turned our attention to the bis-decarbonylation
required for converting 3 to 1. Although there are a number
of conceivable approaches, preliminary investigations fo-
cused on transformations of the corresponding bisamide (14).
The latter was readily available from 3 via treatment with
Scheme 4
conjugate addition to 7-methylcoumarin provided the alky-
lated dihydrocoumarin (12, Scheme 3) in 79% isolated yield.
Hydrolysis of the lactone 12 and in situ conversion to the
triethylamine salt (13) set the stage for the key phenolic
(5) Biernacki, W.; Gdula, A. Synthesis 1979, 1, 37-38.
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Org. Lett., Vol. 8, No. 24, 2006

as a means of generating nitrene species and rearranging them
8
to bisisocyanate 20. As illustrated in Scheme 5, we had
Scheme 5
anticipated the terminal product to be 21, a compound arising
from intramolecular trapping of the tertiary alcohols.9
Although exposure of 15 to BTIB efficiently produced
nitrene 16, it also generated an alkoxy radical. The subse-
quent reactivity was bifurcated and furnished the undesired
ring expansion product 19, confirmed by single X-ray
1
0
analysis (Figure 1).
Figure 1. Structural representation of 19.
As illustrated, this product (19) is believed to arise from
16 via the desired rearrangement and intramolecular trapping
to the cyclic urethane on the left side; concomitantly and in
contrast, the right portion of 16 undergoes ring expansion
to a [2.2.3]bicycle, presumably via radical â-fragmentation.
Su a´ rez et al. have reported similar â-fragmentation of
bicyclo[3.3.0]-carbinolamidyl radicals generated by irradia-
tion with visible light in the presence of hypervalent
1
1,12
organoiodine.
In contrast to Su a´ rez’s substrates, the
fragmentation of 16 delivered a tertiary C-radical that
presumably loses a hydrogen atom to generate enol 18.
ammonia; subsequent addition of one amide moiety into the
nearby ketone delivered cyclic carbinolamide 15 (Scheme
(
8) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.; Blodgett, J.
K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272-4276.
9) Completion of the synthesis from intermediate 21 would require
7
4).
(
We hoped that the cyclic hemiaminal formation would be
hydrolysis of the urethane followed by deamination. For leading references
regarding the latter, see: Barton, D. H. R.; Bringmann, G.; Lamotte, G.;
Motherwell, R. S. H.; Motherwell, W. B. Tetrahedron Lett. 1979, 2291.
reversible, allowing for a potential Hofmann rearrangement
on both amide functional groups of 14 (Scheme 5). To this
end, we explored the use of BTIB in anhydrous acetonitrile
(10) Bravais lattice and space group assignments were unambiguous.
Solution and refinement in the space group P-1 yielded promising initial
results; however subsequent refinements were ineffective, and geometric
parameters deviated significantly from the expected values. The light atom
structure possessed low diffraction intensity (I/σ ) 8.54) despite multiple
data sets from several recrystallizations. The molecule is plagued with
positional disorder in the C(27-32) side chain, and all attempts to effectively
model alternative sites for these atoms were unsuccessful. Without a
successful model, the structure refinement can only afford reliable atom
connectivity.
(6) It is important to note that this homochiral dimerization involves two
stereoselective steps, lactone formation and a Diels-Alder reaction. On
the basis of simple ground-state energy calculations (e.g., MM2 and
MNDO), the product selectivity observed in each step cannot be attributed
solely to product stability. The energetic features underpinning what appear
to be kinetic selectivities have yet to be fully delineated and require
investigation beyond the scope of the current manuscript.
(
7) The yield of this reaction is based on isolation of a mixture of mono-
opened lactones and resubjecting them to the reaction conditions to isolate
5 in 86% combined yield.
(11) Hern a´ ndez, R.; Meli a´ n, D.; Prang e´ , T.; Su a´ rez, E. Heterocycles 1995,
41, 439-454.
(12) Hern a´ ndez, R.; Su a´ rez, E. J. Org. Chem. 1994, 59, 2766-2772.
1
Org. Lett., Vol. 8, No. 24, 2006
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Tautomerization to the corresponding ketone and condensa-
tion with the imide nitrogen furnish enamine 19.
Acknowledgment. We are grateful to the National
Institutes of Health (RO1-CA933591), Amgen, Bristol-Myers
Squibb, Merck, Pfizer, and Yamanouchi for financial support.
We acknowledge and thank C. D. Incarvito (Yale University)
for X-ray crystallographic analysis.
In conclusion, we have developed a highly efficient
phenolic oxidation/Diels-Alder sequence that furnishes the
desired tricyclic skeleton of bacchopetiolone with complete
control of the relative stereochemistry. Although as yet
unsuccessful in delivering 1, decarbonylation attempts have
illustrated the potential utility of BTIB-mediated oxidations
in delivering ring expansion products (e.g., 19 in Scheme
Supporting Information Available: Materials and meth-
1
13
ods, experimental procedures, and H and C NMR and IR
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
5). Current efforts are focusing both on alternatives for
completing the synthesis of 1 and on Su a´ rez fragmentation
modifications.
OL061737H
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Org. Lett., Vol. 8, No. 24, 2006