Studies toward the synthesis of phomactin A. An approach to the macrocyclic core

Article abstract of DOI:10.1016/j.tetlet.2007.04.122

An approach to the macrocyclic core of phomactin A is described. Central to this strategy is the use of a cis-fused oxadecalin intermediate, prepared using the dihydropyrone Diels-Alder reaction. The conformational bias inherent to this system is then use

Full text of DOI:10.1016/j.tetlet.2007.04.122

Tetrahedron Letters 48 (2007) 4605–4607
Studies toward the synthesis of phomactin A. An approach to
the macrocyclic core
Dawei Teng, Bo Wang, Alex J. Augatis and Nancy I. Totah*
Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
Received 12 March 2007; revised 11 April 2007; accepted 24 April 2007
Available online 29 April 2007
Abstract—An approach to the macrocyclic core of phomactin A is described. Central to this strategy is the use of a cis-fused oxa-
decalin intermediate, prepared using the dihydropyrone Diels–Alder reaction. The conformational bias inherent to this system is
then used to facilitate macrocycle formation via an intramolecular B-alkyl Suzuki coupling.
Ó 2007 Elsevier Ltd. All rights reserved.
The phomactins are a group of naturally occurring
diterpenes showing specific PAF antagonist activity.1
Phomactin A (1, Scheme 1),2 the most complex member
of this class, has generated considerable attention from
the organic chemistry community due to its unique
molecular architecture, and the challenge inherent to
its synthesis.3
oxadecalin core would be generated at an early stage of
the synthesis, with subsequent macrocyclization via for-
mation of the trisubstituted olefin. Generation of the
dihydrofuran would then be achieved in the final
stages.5
An obvious concern with this approach lies with the
proximity of reactive functionality (e.g., X and Y in 4)
which must span the fused ring system before bond for-
mation can occur. While the feasibility of such a closure
had been demonstrated in more fully saturated decalin
derivatives,6 the planarity imposed by the enone moiety
(4) is potentially problematic. We anticipated, however,
that the success of such a closure would be favorably
influenced by the inherent conformational bias of a
cyclization precursor such as 4, in which the oxadecalin
ring system is cis-fused. Upon cyclization, subsequent
introduction of the C6 and C7 methyl groups (3) is
expected to occur with high levels of stereoselectivity
as the a-face of the oxadecalin unit is now shielded by
the macrocyclic ring.
Previous efforts from our laboratory have resulted in the
preparation of the reduced furanochroman core of this
natural product.4 Based on these findings, we elaborated
a strategy for the synthesis of phomactin A whereby the
In order to evaluate the potential of such substrates to
facilitate macrocyclization, we set our sights on the syn-
thesis of a simplified tricyclic macrocyle 5. Preparation
of this compound was envisaged via the intermediacy
of bicyclic enone 6, which in turn could be prepared
from an oxadecalin derivative 7 (Scheme 2).
Entry into the oxadecalin system (7) was achieved using
the dihydropyrone Diels–Alder chemistry previously
developed in our laboratory.7 This transformation
accommodates direct incorporation of the requisite C2
vinyl substituent via cycloaddition of dihydropyrone 88
Scheme 1.
*
Corresponding author. Tel.: +1 315 443 2657; fax: +1 315 443
4070; e-mail: ntotah@syr.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.122

4606
D. Teng et al. / Tetrahedron Letters 48 (2007) 4605–4607
Scheme 2.
with the highly oxygenated diene 9 (Scheme 3). Subse-
quent hydrolysis of the intermediate silyl enol ether then
gave oxadecalin 10 as a 1:2 mixture of diastereomers ( ).
*
Here, differential substitution at C2 of the dihydro-
pyrone does not effectively distinguish the two faces of this
dienophile. Reduction of oxadecalone 10 with LiAlH4,
followed by an aqueous acidic workup afforded enone
11, accompanied by small quantities of the correspond-
ing tricyclic ether.9 Protection of the diol then provided
enone 12.
Alternatively, synthesis of enone 12 could be achieved
by a route in which the C2 vinyl function was incorpo-
rated after formation of the oxadecalin core. Thus,
Diels–Alder reaction of dihydropyrone 13 afforded,
upon hydrolysis, oxadecalin 14 as a 2:1 mixture of dia-
stereomers, now favoring the desired stereoisomer
(Scheme 4). Incorporation of the hydroxyethyl side
chain at C2 of the dihydropyrone may ultimately pro-
vide a means to impart stereoselectivity to this transfor-
mation by serving as an itinerant tether in an
intramolecular cycloaddition process.
Scheme 4.
Oxadecalin 14 was converted to enone 16 by a reduc-
tion/protection sequence analogous to that described
above (cf. Scheme 3). Incorporation of the C2 vinyl
function was then initiated by cleavage of the benzyl
protecting group. Under conditions of palladium cata-
lyzed hydrogenation, deprotection of the primary alco-
hol was accompanied by reduction of the enone
leading to formation of ketone 17.10 Elimination of
the primary alcohol was effected under Grieco–Sharp-
less conditions11 providing ketone 18, with subsequent
reintroduction of the C6/C7 double bond giving enone
12. Though slightly longer, this route proceeds in an
overall yield comparable to that first described.
With enone 12 in hand, further functionalization of the
oxadecalin core required introduction of the C6 side
chain (Scheme 5). As such, halogenation of enone 12
provided vinyl iodide 19, which was subjected to a B-
alkyl Suzuki coupling12 with the organoboron reagent
derived from alkyne 20 to give the trisubstituted enone 6.
From here, macrocyclization substrate 21 was generated
by manipulation of the terminal alkyne 6 by deprotec-
tion, followed by a hydrozirconation/iodination se-
quence. Macrocyclization was then effected via Suzuki
coupling13 under high dilution conditions to give the de-
sired product 5 in a respectable 48% yield. While at first
glance, cyclization of a substrate (21) having an sp2
hybridized center at C6 seems contrary to a successful
macrocyclization, the cis-fused ring system orients the
substrate such that there is little strain associated with
ring formation.
In conclusion, we have demonstrated feasibility of
generating the 12-membered macrocycle found in
phomactin A using substrates of type 6 that contain
unsaturation at C5–C7. The cis ring fusion of the
preformed oxadecalin core is central to this strategy,
helping to orient reactive functionality and facilitate
macrocyclization. Ongoing efforts in our laboratories
are aimed at the total synthesis of phomactin A. These
results will be reported in due course.
Scheme 3.

D. Teng et al. / Tetrahedron Letters 48 (2007) 4605–4607
4607
Scheme 5.
Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125,
1712; (n) Diaper, C. M.; Goldring, W. P. D.; Pattenden,
G. Org. Biomol. Chem. 2003, 3949.
Acknowledgments
Support from the National Institutes of Health, Institute
of General Medical Sciences (R01 GM064357) is grate-
fully acknowledged.
4. Seth, P. P.; Totah, N. I. Org. Lett. 2000, 2, 2507.
5. This approach stands in contrast to those generally set
forth by other researchers in which formation of the
pyrone unit is effected after macrocycle formation. Excep-
tions are found in the work of Hsung (Ref. 3j) and
Halcomb (Ref. 3m). In the former case, pyrone and
macrocycle are formed concurrently. In the latter, macro-
cyclization is effected with the oxadecalin system in place,
albeit in modest yield.
6. Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695,
See also (Ref. 3m).
7. (a) Chen, D.; Wang, J.; Totah, N. I. J. Org. Chem. 1999,
64, 1776; (b) Seth, P. P.; Totah, N. I. J. Org. Chem. 1999,
64, 8750; (c) Seth, P. P.; Chen, D.; Wang, J.; Gao, X.;
Totah, N. I. Tetrahedron 2000, 56, 10185.
Supplementary data
Experimental procedures and characterization data for
compound 5 and all key intermediates. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.04.122.
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