A fully synthetic route to the neurotrophic illicinones by sequential aromatic Claisen rearrangements [10]

Full text of DOI:10.1021/ja982582e

12684
J. Am. Chem. Soc. 1998, 120, 12684-12685
Scheme 1. Interconversions in the Illicinone Seriesa
A Fully Synthetic Route to the Neurotrophic
Illicinones by Sequential Aromatic Claisen
Rearrangements
Thomas R. R. Pettus,*,† Xiao-Tao Chen,† and
Samuel J. Danishefsky†,‡
a (a) 450 W Hg lamp, 30 min., 3 f 2 (7%) + 1 (5%) or 2 f 1 (28%);
(b) 200 °C, 4 h, 2 f 4 (50%).
Department of Chemistry, Columbia UniVersity
3000 Broadway, New York, New York 10027
Laboratory for Bioorganic Chemistry
Scheme 2
Sloan-Kettering Institute for Cancer Research
1275 York AVe., Box 106, New York, New York 10021
ReceiVed July 21, 1998
Fukuyama and colleagues have rcently reported the isolation
of tricycloillicinone (1) from Illicium tashiroi.1 Illicinone, 2, also
obtained from Illicium tashiroi, might be a biosynthetic precursor
of 1. Indeed, in an earlier investigation, photolysis of 2 had been
shown to afford 1.2 Interestingly, compound 2 and its photo
product 1 were available from photolysis of 3,3 the prenylation
product of 4. Compound 4 itself is obtained from the pyrolysis
of 2 (Scheme 1).
Scheme 3a
The illicinones are members of an intriguing class of “small
molecule” neurotrophic factors. Fukuyama has shown that such
compounds exhibit their effects through increased choline acetyl-
transferase (ChAT) activity,4 resulting in the enhanced sprouting
during the development of neurons in a primary culture of fetal
rat cerebral tissues.5 Small molecule neurotrophic factors could
conceivably be of at least palliative value in Alzheimer’s disease,
which is characterized by markedly reduced ChAT function.6
To implement our proposed strategy effectively, it was neces-
sary to accomplish, with conciseness, the synthesis of substrates
for aromatic Claisen rearrangements and to control the rearrange-
ment step itself in the context of extensively oxygenated
matrixes.7,8 For instance, a direct synthesis of 5 from methylene-
dioxyresorcinol is complicated by a lack of control in either
phenolic allylation or silyl protection.9 As will be seen, we solved
this problem through the use of a carbomethoxy group as a sur-
rogate for the hydroxy residue following the precedent of Boger
and Coleman (see sequence starting with 12).10
a (a) PhSO2CH(CH2Br)2, K2CO3, acetone, rt, 85%; (b) neat, 165 °C,
12 h, 94%; (c) K2CO3, acetone, ∆, >95%; (d) 10% Na-Hg, MeOH-
EtOAc, -20 °C, 87%.
the Cope step is apparently competitive with simple tautomer-
ization of 11, which would have given 7 or 9.11
We wondered about the consequences of placing a group at
C2 of the allyl function, with respect to the ortho:para ratio in
the Claisen rearrangement. In this connection, we synthesized
compound 13 by alkylation of 12 with 1,3-dibromo-2-phenylsul-
fonylpropane as shown.12,13 Thermolysis of 13, neat, at temper-
atures as low as even 165 °C, gave Claisen rearrangement.
Interestingly, the only isomer observed under these thermal
conditions was the ortho product, 14 (94% yield). Following
considerable difficulties in unveiling the allyl group of the desired
9 through attempted reductive cleavage of the sulfone function
in 14, an additional modification was introduced. When the
Claisen rearrangement was conducted in the presence of potassium
2,6-dimethylphenoxide, a 94% yield of the benzopyran 15, was
obtained.14 Presumably, under these conditions, compound 15
arises from base-induced Michael type cyclization of previously
isolated 14. Indeed, such a cyclization was independently achieved
on isolated thermolysis product 14 through the action of potassium
carbonate. Exposure of 15 to the action of sodium mercury
amalgam produced 9 in 86% yield15 (Scheme 3). Thus, Michael
Furthermore, the principal rearrangement products of 5 and 6
were the para products 8 and 10, rather than the desired ortho
isomers 7 and 9 (Scheme 2). The tendency for the formation of
para-Claisen products in such systems is well precedented.7
Seemingly, 8 and 10 are produced from Cope rearrangement of
11, the presumed intermediate in the ortho route. Remarkably,
(1) Fukuyama, Y.; Shida, N.; Kodama, M.; Chaki, H.; Yugami, T. Chem.
Pharm. Bull. 1995, 43, 2270.
(2) Yakushijin, K.; Sekikawa, J.; Suzuki, R.; Morishita, T.; Furukawa, H.;
Murata, H. Chem. Pharm. Bull. 1980, 28, 1951.
(3) Yakushijin, K.; Furukawa, H.; McPhail, A. T. Chem. Pharm. Bull. 1984,
32, 23. A tetracyclic structure (ring closure instead of H abstraction) is
produced along with tricycloillicinone in 21%, see compound 6 in this citation.
(4) Delivery of exogenous protein factors to the CNS remains one of the
major obstacles for trophic factor therapy. The discovery of cell permeable
small trophic molecules represents a potential frontier in research directed at
neurodegenerative diseases. Rosenburg, S. Section I: CNS Reagents. Annual
Reports in Medicinal Chemistry-27; Academic Press: New York; 1992, p
41.
(5) Furukawa, H.; Shida, N.; Kodama, M. Planta Med. 1993, 59, 181.
(6) Hefti, F. J. Neurobiol. 1994, 25, 1418.
(7) Rhoads, S. J.; Raulins, N. R. Organic Reactions; John Wiley & Sons:
New York, 1975; Vol. 22, p 1.
(8) The consecutive rearrangement strategy practiced here uses the same
aromatic hydroxyl to direct rearrangements to the two flanking ortho centers.
This is to be distinguished from the concept of tandem rearrangements; see:
Ziegler, F. E. Chem. ReV. 1988, 88, 1423.
(9) (a) Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48, 1941.
(b) Schneider, G. E.; Stevenson, R. J. Org. Chem. 1981, 46, 2969. (c)
McKittrick, B. A.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1 1984, 709.
(10) Boger, D.; Coleman, R. S. J. Org. Chem. 1986, 51, 5436.
(11) The ortho products do not rearrange to the para isomers. Seemingly,
therefore, the para:ortho ratios are under kinetic control.
(12) Compound 12 was prepared as previously reported in one step from
methyl gallate, see: Keseru¨, G. M.; No´gra´di, M.; Kajta´r-Peredy, M. Liebigs
Ann. Chem. 1994, 361; cf. Kuo, G.-H.; Eissenstat, M. A. Tetrahedron Lett.
1997, 38, 3343.
(13) For the preparation of 1,3-dibromo-phenylsulfonylpropane, see: (a)
Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 425. (b) Auvray, P.;
Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 4455.
(14) For a previous example of the conduct of a Claisen rearrangement in
the presence of base, see: Nakatsubo, F.; Cocuzza, A. J.; Keeley, D. E.; Kishi,
Y. J. Am. Chem. Soc. 1977, 99, 4835.
10.1021/ja982582e CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/09/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12685
Scheme 4a
a (a) 4 equiv 1.4 M [MeLi-LiBr], THF, 12 h, 90%; (b) (CH3)2C(Cl)CCH, Kl, K2CO3, acetone, 60 °C, 48 h, 73%; (c) 50% H2O2:H2SO4 (5:4),
CH2Cl2, 10 min, 60-85%; (d) TBDPSCl, imidazole, DMAP, CH2Cl2, >97%; (e) 10 mol% Pd-CaCo3 (Pb-poisoned), quinoline, EtOAc, >95%; (f)
toluene, 100 °C, 2 h, >95%.
like cyclization followed by reductive ring opening under condi-
tions where Cope rearrangement or re-cyclization does not occur,
was used to produce 9 with positional control.
Scheme 5a
With this seemingly minor, but actually serious problem solved,
we could direct our attentions to the second Claisen step. Once
again, experience constrained us to follow a narrow pathway.
Addition of excess methyllithium to 9 produced 16. The latter
could be alkylated with 3-chloro-3-methyl-1-butyne under ca-
talysis with KI, giving rise to an 87% yield of 17.16 Subjection
of this compound, at 0 °C, to the action of a mixture of hydrogen
peroxide and sulfuric acid (5:4) produced 19. The latter, upon
silylation, provided 20. We presume that the oxidative fragmenta-
tion of 17, anticipated by the Boger-Coleman precedent,10 arises
from an exchange process leading to the formation, in situ, of
the cumyl hydroperoxide, 18. Criegee-like rearrangement of the
latter provided 19. Lindlar reduction of 20 afforded 21 which
underwent smooth rearrangement at 100 °C in toluene to produce
2217 (Scheme 4).
Compound 22, which is essentially an oxidized version of
illicinone, serves as a general intermediate for reaching a variety
of compounds in this series. For instance, treatment of 22 with
L-Selectride, followed by acetylation and â-elimination provided
2 itself. Photolysis of illicinone, indeed, produced tricycloillicinone
(1) as previously described.3 In our hands thus far, however, this
reaction occurs in only 10-15% yields.
a (a) 2 equiv Mn(OAc)3‚H2O, 1 equiv Cu(OAc)2‚H2O, HOAc, 50 °C,
3 h, 70-80%; (b) i. L-Selectride, THF; ii. Ac2O, DMAP, 82% overall;
(c) neat DBU, rt, 1 h, 65%; (d) degassed Et2O, 450 W Hg lamp, pyrex
tube, 1 h, 10-15% (see ref 3); (e) LiAlH(O-t-Bu)3, THF, 78%; (f)
KHMDS, THF, -78 °C, then salt of DAMP and PhOC(S)Cl, -20 °C,
overnight, 90%; (g) Bu3SnH, AlBN, benzene, ∆, overnight, 42%.
Of greater value is the fact that heating of compound 22 with
manganese(III) and copper(II) acetates, smoothly gave rise to 24.
Presumably during this reaction, the silyl enol ether was cleaved.
The resultant â-diketone (which corresponds electronically to a
vinylogous â-ketoester) then undergoes oxidative cyclization in
the fashion developed by Corey and Snider.18 Selective reduction
of the ketone at the C1 bridge and deoxygenation of the resultant
alcohol as shown, led to 1. In addition to producing the natural
product in a more pleasing fashion, this route provides access to
a wealth of analogue structures (Scheme 5).
of ortho to para Claisen rearrangement products in complex
oxygenated systems in favor of the former (see compound 9).
The cumyl hydroperoxide rearrangement reaction simplified the
otherwise difficult problems associated with differentiation of
multiple oxygen functions in reaching pre-Claisen precursor 21.
Finally, application of the Snider reaction (22 f 24) provides a
direct route to tricycloillicinone.
Acknowledgment. This work was supported by the NIH (Grant
Numbers: HL25848 (S.J.D.) and CA08748 (S.K.I. Core Grant)). T.R.R.P.
gratefully acknowledges the NSF for a Postdoctoral Fellowship (Grant
Number: CHE96-26443). We are grateful to Vinka Parmakovich and
Barbara Sporer of the Columbia University Mass Spectral Facility for
their measurements.
At the chemical level our route to these small molecule
neurotrophic agents illustrates a method to control the distribution
(15) Cf.: Kocienski, P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkins
Trans. I 1978, 829.
(16) Hennion, G. F.; Sheehan, J. J.; Maloney, D. E. J. Am. Chem. Soc.
1950, 72, 3542 and references therein.
(17) Cf. Murray, R. D. H.; Sutcliffe, M. Tetrahedron 1975, 31, 2966.
(18) Cf. (a) Corey, E. J.; Kang, M.-C. J. Am. Chem. Soc. 1984, 106, 5384.
(b) Snider, B. B. Chem ReV. 1996, 93, 339. (c) Kates, S. A.; Dombroski, M.
A.; Snider, B. B. J. Org. Chem. 1990, 55, 2427. (d) Snider, B. B.; Merritt, J.
E.; Dombroski, M. A.; Buckman, B. O. J. Org. Chem. 1991, 56, 5544. (e)
Snider, B. B.; Mohan, R.; Kates, S. A. J. Org. Chem. 1985, 50, 3659.
Supporting Information Available: Experimental procedures for
compounds (1, 2, 9, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24) are provided
(5 pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
JA982582E