Solid-phase biomimetic synthesis of carpanone-like molecules

Full text of DOI:10.1021/ja993674m

422
J. Am. Chem. Soc. 2000, 122, 422-423
Scheme 2
Solid-Phase Biomimetic Synthesis of Carpanone-like
Molecules
Craig W. Lindsley, Lawrence K. Chan, Brian C. Goess,
Reni Joseph, and Matthew D. Shair*
Department of Chemistry & Chemical Biology
HarVard UniVersity, 12 Oxford St.
Cambridge, Massachusetts 02138
HarVard Institute of Chemistry & Cell Biology
HarVard Medical School, Boston, Massachusetts 02136
ReceiVed October 13, 1999
The advances of split-pool organic synthesis1 and high-
throughput biological screens2 have provided new opportunities
for the discovery of man-made molecules with novel biological
properties. Realization of these new opportunities will be ac-
celerated by the development of solid-phase reactions that
dramatically increase molecular complexity while simultaneously
accessing diverse structures. Biomimetic reactions that mimic
natural product biosyntheses3 are well suited to this approach
because they often convert simple starting materials to complex
structures under mild conditions. While this is an attractive
concept, two significant challenges are (1) developing biomimetic
transformations that access a diverse range of structures and (2)
performing these reactions in the solid-phase. This communication
reports the development of biomimetic reactions in the solid-phase
that result in one-step construction of tetracyclic molecules from
readily accessible starting materials. The reactions are based on
ones implicated in the biosynthesis of carpanone and other
members of the benzoxanthenone class of natural products.4
The biomimetic synthesis of carpanone (Scheme 1, [O] )
PdCl2), first accomplished by Chapman, occurs by diastereose-
lective oxidative homocoupling of an electron-rich o-hydroxy-
styrene followed by rapid endo-selective inverse electron demand
Diels-Alder cycloaddition.5 To broaden the scope of this
those isolated from nature, it was necessary to develop a reaction
that would result in intermolecular oxidative heterodimerization
of dissimilar o-hydroxystyrenes. To our knowledge, this level of
selectivity has not been observed for â,â-phenolic couplings in
natural or laboratory systems.
Our plan involved the use of electronically differentiated
o-hydroxystyrenes (Scheme 2). Under the influence of a suitable
oxidant, the oxidatively more reactive electron-rich phenol 2,
immobilized in the solid-phase to reduce its propensity for
homodimerization, will react preferentially with the oxidatively
less reactive electron-deficient phenol 1 in solution.6 Following
oxidative heterocoupling, inverse electron demand Diels-Alder
transition states 3 and 4 are possible. The electronically preferred
transition state 4 should be favored affording tetracycle 5 directly.7
In a single biomimetic reaction in the solid-phase, tetracyclic
molecules will be constructed with control over five stereocenters
and four initial positions of diversity (R1-R4).
Scheme 1
Initially, we screened a series of oxidants for their ability to
cross-couple electronically differentiated substrates 6 and 78
(Scheme 3). Only PhI(OAc)2 afforded heterocoupled product 8.9
All other oxidants tested resulted in exclusive formation of 9,
resulting from intrabead homocoupling.10 It is interesting to note
that PhI(OAc)2 was the only oxidant in the screen that did not
proceed through a phenoxy radical intermediate.11
Following HF-pyridine promoted removal from the solid-
phase (0.15 mmol/g) a 55% yield of tetracycle 8 was isolated as
a single isomer, resulting from complete electronic control of the
inverse electron demand cycloaddition. The solid-phase reaction
afforded a 1.7:1 ratio of heterocoupled adduct 8 and homocoupled
adduct 9 starting from silicon-linked resin 7 (Entry B). Compound
(6) For intermolecular oxidative biaryl heterocoupling, see: (a) Young, D.
A.; Young, E.; Roux, D. G.; Brandt, E. U.; Ferreira, D. J. Chem. Soc., Perkin
Trans. 1 1987, 2345. (b) Hovorka, M.; Gunterova, J.; Zavada, J. Tetrahedron
Lett. 1990, 31, 413.
(7) The preference for transition state 4 is based upon the strong preference
of acrolein for ethyl vinyl ether over itself in an inverse electron demand
heterocycloaddition reaction. For examples, see: Longley, R. I.; Emerson,
W. S. J. Am. Chem. Soc. 1950, 72, 3079.
biomimetic synthesis, with the goal of constructing a split-pool
synthesis library of carpanone-like molecules more diverse than
(1) (a) Furka, A.; Sebestyen, F.; Asgedom, M.; Dibo, G. Int. J. Pept. Protein
Res. 1991, 37, 487-493. (b) Lam, K. S.; Salmon, S. E.; Hersh, E. M.; Hruby,
V. J.; Kazmierski, W. M.; Knapp, R. J. Nature 1991, 354, 82-84. (c) Nicolaou,
K. C.; Pastor, J.; Winssinger, N.; Murphy, F. J. Am. Chem. Soc. 1998, 120,
5132-5133. (d) Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. J.
Am. Chem. Soc. 1998, 120, 8565-8566.
(8) Hu, Y.; Porco, J. A., Jr.; Labadie, J. W.; Gooding, O. W. J. Org. Chem.
1998, 63, 4518-4521.
1
(2) For a recent review of high-throughput biological screening, see:
Fernandes, P. B. Curr. Opin. Chem. Biol. 1998, 2, 597-603.
(3) Braun, M. Org. Synth. Highlights 1991, 232-9.
(9) All new compounds were fully characterized by H NMR, 13C NMR,
IR, and HRMS. See the Supporting Information for details.
(10) PdCl2-NaOAc, Co(Salen)-O2, Mn(Salen)-O2, CuCl2-tBuNH2, Fe-
(Salen)-O2, O2-hν-rose bengal, PhI(OCOCF3)2, and VOF3 led exclusively to
homodimerization. Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1981, 22,
4437.
(4) (a) Brophy, G. C.; Mohandas, J.; Slaytor, M.; Sternhell, S.; Watson, T.
R.; Wilson, L. A. Tetrahedron Lett. 1969, 10, 5159-5162. (b) Jakupovic, J.;
Eid, F. Phytochemistry 1987, 26, 2427-2429.
(5) Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am.
Chem. Soc. 1971, 93, 6696.
(11) Varvoglis, A. Best Synthetic Methods: HyperValent Iodine in Organic
Synthesis; Academic Press: New York, 1997.
10.1021/ja993674m CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/31/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 2, 2000 423
Scheme 3a
Scheme 4a
a Conditions: (a)10 equiv of 6, PhI(OAc)2, CH2Cl2-THF, agitation,
25 °C, 2 h. (b) For Si-linker: HF-pyridine, THF, 25 °C, then TMSOMe.
For Trityl linker: 2% TFA, 20% Et3SiH, CH2Cl2.
a Conditions: (a) 10 equiv of 10, PhI(OAc)2, CH2Cl2-THF, agitation,
25 °C, 2 h. (b) HF-pyridine, THF, 25 °C, then TMSOMe. Isolated yields
are based upon resin 7. For R, see entry C, Scheme 3.
9 resulted from an oxidative homocoupling between two mol-
ecules of 7 attached to the same resin bead. Although lowering
the loading level of the resin resulted in a modest reduction in
intrabead reactions for entry B (Scheme 3) (0.3 mmol/g f 1:1
8/9; 0.15 mmol/g f 1.7:1 8/9; 0.075 mmol/g f 4:1), it was
crucial that the loading level remain as high as possible to facilitate
future biological screens. As a result of these issues combined
with the lack of detailed information regarding the orientation of
molecules attached to the solid-phase, the factors contributing to
intrabead coupling, excluding resin loading levels, had to be
determined on an empirical basis.12 A diminution in homocoupling
was observed when R contained amide bonds. For instance, the
silicon-based linker combined with an amide-based spacer (entry
C) provided the highest degree of heterocoupled product (5.3:1)
at a loading level of 0.15 mmol/g, whereas the silicon linker and
a hydrocarbon spacer (entry B) afforded only a slight preference
for heterocoupling (1.7:1). A trityl-based linker and an amide
spacer (entry A) afforded a 1:1 ratio of 8 and 9 (Scheme 3).
To explore the generality of the solid-phase biomimetic reaction
for diversity-oriented synthesis, a series of electron-deficient
phenols were constructed and tested in the solid-phase synthesis
(Scheme 4). Electron-withdrawing groups in the Y position of
10 that led to productive solid-phase heterocoupling included
amides (entries A and B), ester (entry C), activated ester (D),
and acylated phenol (entry E). The X position tolerated alkyl and
heteroatom containing groups with isolated yields between 77
and 81%. In each case, the tetracyclic adducts were obtained as
single isomers resulting from complete electronic control during
the inverse electron demand Diels-Alder cycloadditions. A small
(∼10%) amount of compound 9, resulting from dimerization of
7, was also isolated from these experiments.
In conclusion, biomimetic solid-phase synthesis of carpanone-
like molecules has been accomplished. Combining an amide-based
linker and silyl attachment to the solid-phase diminished compet-
ing intrabead coupling. These results highlight the intriguing
possibility of controlling reactions in the solid-phase by altering
the structure of the linker.13 In the six experiments reported in
this study, the biomimetic solid-phase reaction tolerated a range
of functionality, making it amenable to diversity-oriented synthesis
and construction of libraries of carpanone-like molecules. Experi-
ments are underway to functionalize the carpanone-like com-
pounds in the solid-phase en route to split-pool synthesis of a
100,000-member library and high-throughput biological screens.14
We are also investigating the correlation between solid-phase
linker structure and the control of site-site interactions in the
solid-phase.
Currently, biomimetic reactions and syntheses are used to
access a single natural product. If biomimetic reactions are
generalized, for the purpose of diversity-oriented synthesis, and
combined with split-pool synthesis techniques, they may become
a powerful method of constructing a wide range of natural
product-like structures for discovery of molecules with new
biological properties.
Acknowledgment. Financial support from the NCI (5-P01-CA78048),
Merck & Co., Pharmacia & Upjohn, SmithKline Beecham, the Corning
Fund, The Medical Foundation, and HFSP (RG-293/98) is gratefully
acknowledged. B.G. acknowledges an NDSEG fellowship.
(12) Intrabead reactions have been observed and a reduction of intrabead
interactions can be achieved on an adhoc basis by lowering the loading level
of the resin. For a discussion, see: (a) Rapoport, H.; Crowley, J. I. Acc. Chem.
Res. 1976, 9, 135-144. (b) Yan, B. Combinatorial Chem. High Throughput
Screening 1998, 1, 215-229.
Supporting Information Available: Details of experimental proce-
dures and analytical data (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) Tollner, K.; Biro-Popovitz, R.; Lahav, M.; Milstein, D. Science 1997,
278, 2100.
(14) For the synthesis of nonnatural carpanone-like molecules with biologi-
cal activity, see: Maeda, S.; Masuda, H.; Tokoroyama, T. Chem. Pharm. Bull.
1995, 43, 935-940.
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