An interesting issue of Diels-Alder selectivity discovered en route to 11-O-debenzoyltashironin

Article abstract of DOI:10.1021/ol062067i

(Diagram presented) The hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade was examined in the context of the natural product 11-O-debenzoyltashironin. Interestingly, the regioselectivity of the Diels-Alder reaction can be completely switched by changing the dienophile. Trapping of allyl alcohols during the oxidative dearomatization gives rise to the five-membered acetal, while trapping of allenyl alcohols results in the six-membered acetal.

Full text of DOI:10.1021/ol062067i

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5693-5695
An Interesting Issue of Diels−Alder
Selectivity Discovered En Route to
11-O-Debenzoyltashironin
Silas P. Cook† and Samuel J. Danishefsky*,†,‡
Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway,
New York, New York 10027, and the Laboratory for Bioorganic Chemistry,
Sloan-Kettering Institute for Cancer Research, 1275 York AVenue,
New York, New York 10021
s-danishefsky@ski.mskcc.org
Received August 22, 2006
ABSTRACT
The hypervalent iodine-mediated oxidative dearomatization/Diels−Alder cascade was examined in the context of the natural product 11-O-
debenzoyltashironin. Interestingly, the regioselectivity of the Diels−Alder reaction can be completely switched by changing the dienophile.
Trapping of allyl alcohols during the oxidative dearomatization gives rise to the five-membered acetal, while trapping of allenyl alcohols
results in the six-membered acetal.
In the context of our ongoing interest in the synthesis and
biological evaluation of neurotrophically active small mol-
ecules,1 we recently launched an effort directed toward the
total synthesis of the anistatin-related natural product, 11-
O-debenzoyltashironin (1) (Figure 1). Isolated from the
exhibits no observable neurotrophic activity.3 Aside from our
anticipation that 1 is a potentially valuable lead candidate
in the development of a neurotrophic agent, we were
particularly drawn to issues of chemical interest in attempting
to synthesize the highly oxygenated, densely functionalized
core structure of 11-O-debenzoyltashironin.
The initial task would be that of assembling a [2.2.2]
bicyclic core, appropriately functionalized for installation of
the remaining structural features of the molecule. We
describe herein our investigations into an oxidative dearo-
matization-Diels-Alder cascade strategy to allow for the
assembly of the core structure.
The Tamura-Pelter oxidation,4 originally conceived of as
a means of access to p-quinone dialkyl monoketals through
oxidative dearomatization of phenols in methanol, was further
advanced by the pioneering work of Liao to include intermolec-
ular trapping by various allylic alcohols with subsequent
Diels-Alder cyclization.5 Our strategy for the assembly of
the tashironin core, outlined in Scheme 1, envisioned recourse
Figure 1. 11-O-Debenzoyltashironin (1) and tashironin (2).
Eastern Asian Illicium merrillianum, 1 has been shown to
promote neurite outgrowth at concentrations as low as 0.1
µmol.2 Interestingly, its benzoylated congener, tashironin (2),
(2) Huang, J. M.; Yokoyama, R.; Yang, C. S.; Fukuyama, Y. J. Nat.
Prod. 2001, 64, 428.
(3) Fukuyama, Y.; Shida, N.; Kodama, M. Tetrahedron Lett. 1995,
36, 583.
† Columbia University.
‡ Sloan-Kettering Institute for Cancer Research.
(1) For a recent account of our laboratory’s involvement in this area,
see: Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539.
(4) (a) Tamura, Y.; Yakura, T.; Haruta, J. I.; Kita, Y. J. Org. Chem. 1987,
52, 3927. (b) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677.
10.1021/ol062067i CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/16/2006

Scheme 1. Proposed Oxidative Dearomatization-Diels-Alder
Scheme 3. Oxidative Dearomatization-IMDA of 11
Cascade
to this powerful, complexity building sequence. It was antici-
pated that intermolecular oxidative dearomatization of 3, in
the presence of an allenyl alcohol, would provide the o-quinone
intermediate, 4. We hoped that the latter would undergo spon-
taneous intramolecular Diels-Alder cyclization to provide the
tashironin core, 5. This rapidly assembled complex intermedi-
ate would be equipped with the pendant functionality required
for the completion of the synthesis of the natural product.
The synthesis of the requisite aromatic substrate, 11,
commenced with vanillyl alcohol (6). Treatment of the latter
with a catalytic amount of tosyl acid in methanol served to
methoxylate the presumed transient p-quinone methide
intermediate (Scheme 2). Installation of the aromatic methyl
The successful implementation of our strategy would require
intermolecular trapping of the allenyl alcohol through oxida-
tive dearomatization. This step would be followed by intra-
molecular Diels-Alder reaction with the internal olefin of the
allenol. In contemplating this approach, we were aware of
potential issues of regioselectivity in the Diels-Alder reaction.
In the event, when phenol 11 was combined with PIFA
and an excess of allenyl alcohol 12, a single Diels-Alder
product was observed. It was shown to be the undesired
acetal product 14 rather than 15 (which would have cor-
Scheme 2. Synthesis of Phenol 11
Table 1. Allenyl Alcohol Diels-Alder Reaction
group at the more hindered position was achieved through
chelation-controlled aryl lithiation with subsequent alkylation.
DDQ-mediated oxidation afforded 7 in 54% overall yield.
Hydroxyl-directed bromination of 7 provided phenol 8.
Benzylation followed by m-CPBA-mediated Baeyer-Villiger
oxidation generated an intermediate formate, which upon
hydrolysis gave rise to phenol 9 (63% yield over three steps).
Finally, tosylation followed by benzyl deprotection yielded
the desired substrate 11 in 98% yield.
Allenyl alcohols 12 and 13 were prepared from the
corresponding propargyl halides, as shown in eq 1.6
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Org. Lett., Vol. 8, No. 25, 2006

from an allenyl to an allyl system, the direction of the
reactions was completely reversed and only the 5-membered
acetal could be detected in the latter case (Table 2). As with
the allenyl alcohols, modifications of the aromatic ring
system did not alter the sense of the Diels-Alder reaction
(Table 2).
Table 2. Allyl Alcohol Diels-Alder Reaction
With the benefit of retrospection, an accounting of the
dramatic differences in the results in Tables 1 and 2 can be
offered. It seems likely that, from a perspective of steric strain
in the product (and of the transition state leading to it), the
formation of the 5-membered acetal would be preferred over
the 6-membered product, with its additional torquing of the
acetal carbon. However, in the allene cases there is a strong
preference for initial partial bond formation between the
unique sp carbon of the dienophile with C4 of the dienone.
In this way, radicaloid character in the transition state is
supported by the tosylate at C3 and the bromine at C1, as
well as its connected ketone. Given the orienting affinity
between C4 and the sp carbon, the formation of Table 1
products is dictated.
In conclusion, hypervalent iodine-mediated oxidative
dearomatization was used to form high energy [4 + 2]
precursor systems that readily undergo intramolecular Diels-
Alder reaction (Figure 2). Highly substituted, unactivated
responded to a possible pre-tashironin intermediate) (Scheme
3). The 6-membered acetal could not, however, be exploited
toward reaching tashironin.
Thus, we probed the scope of this undesired pathway by
investigating the consequences which perturbations of the
aromatic ring substituents might have on the regiochemical
outcome of the IMDA reaction with allenyl dienophiles.
Substrates were prepared in which the tosyl ester was
replaced with a methyl ester group (Table 1, entries 2 and
5) and the methyl ether was replaced with a benzyl ether
(Table 1, entry 4). In practice, reaction of each of these
modified substrates with allenol 12 provided the 6-membered
acetal IMDA adduct. When allenyl alcohol 13 was used as
the dienophilic coupling partner with phenol 11 (Table 1,
entry 1), a crystalline product was obtained. X-ray analysis
of the compound revealed unambiguously the 6-membered
acetal product.7
Figure 2. IMDA reactions of allenic and olefinic intermediates.
dienes are used in the reaction to produce complex Diels-
Alder adducts. Additionally, the regioselectivity of cycliza-
tion can be controlled by judicious choice of dienophile.
Applications of these findings are being pursued.
Acknowledgment. Support for this research was provided
by the National Institutes of Health (HL25848).
We sought to explore the outcome of reactions with
simpler dienophiles. Interestingly, by changing the dienophile
Supporting Information Available: Experimental pro-
cedures and physical data for compounds 6-14 and Diels-
Alder cycloadducts. This material is available free of charge
via the Internet at http://pubs.acs.org.
(5) Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856 and
references cited therein.
(6) Isaac, M. B.; Chan, T-H. J. Chem. Soc., Chem. Commun. 1995, 1003.
(7) Crystallographic data (excluding structural data) for the cycloaddition
product in Table 1, entry 1, have been deposited with the Cambridge
Crystallographic Data Centre (CCDC as Deposition No. CCDC 61734).
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