Radical and palladium-catalyzed cyclizations to cyclobutenes: An entry to the BCD ring system of penitrem D

Article abstract of DOI:10.1021/jo049873s

A novel approach toward the synthesis of the BCD ring system of penitrem D is described. The strategy capitalizes on the fast cyclization rates of aryl radicals into cyclobutenes and allows access to a variety of fused tricyclic structures. Radical/polar

Full text of DOI:10.1021/jo049873s

Ra d ica l a n d P a lla d iu m -Ca ta lyzed Cycliza tion s to Cyclobu ten es:
An En tr y to th e BCD Rin g System of P en itr em D
Alexey Rivkin, Felix Gonza´lez-Lo´pez de Turiso, Tadamichi Nagashima, and
Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
curran@pitt.edu
Received J anuary 22, 2004
A novel approach toward the synthesis of the BCD ring system of penitrem D is described. The
strategy capitalizes on the fast cyclization rates of aryl radicals into cyclobutenes and allows access
to a variety of fused tricyclic structures. Radical/polar crossover reactions of precursors 24-29
promoted by samarium diiodide in the presence of HMPA and acetone allow access to the fully
functionalized BCD ring system of penitrem D. The stereochemical implications of these processes
are evaluated, and a Pd-mediated cyclization approach toward the penitrems is also introduced.
In tr od u ction
The penitrems represent a class of novel indole alka-
loids that have attracted attention as a result of their
potent neurotoxic activity and complex architectures.1
The structures of this family of compounds feature nine
interlocking rings, including both a cyclobutane and an
eight-membered cyclic ether, as well as eleven stereogenic
centers (Figure 1). The juxtaposition of rings B-F on the
periphery of ring A represents a significant synthetic
challenge to existing methodology that has recently been
met by Smith and co-workers.2
We have been interested in the development of novel
radical cyclization approaches toward the construction
of the unusual A-F ring core present in the penitrems.3
Central to our investigations has been the development
of a radical/polar crossover reaction of a precursor 14,5
that could provide access to the fully functionalized BCD
ring system of penitrem D 2 with different substituents
R1, R2 in the ring C (Figure 2). In the planned synthetic
strategy, we generate an aryl radical 3 from a precursor
1 that is expected to undergo a 6-exo-trig cyclization into
the cyclobutene to give an intermediate cyclobutyl radical
F IGURE 1. Structure of penitrem D.
4. This intermediate is further reduced under the reac-
tion conditions (SmI2‚HMPA, acetone) to the correspond-
ing cyclobutyl samarium species 5 (or its equivalent),
which then adds to acetone to provide the corresponding
samarium alkoxide 6. Aqueous workup of the reaction
mixture provides the target alcohol 2 (Figure 2).6,7 A key
feature of this synthetic approach is the ability of a
cyclobutene to intercept an aryl radical in an intra-
molecular fashion. Although cyclobutenes are expected
to be good radical acceptors8 and have been used in
bimolecular reactions,9 we could not locate any examples
(6) (a) Krief, A.; Laval, A. M. Chem. Rev. 1999, 99, 745-778. (b)
Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307-338. (c)
Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321-3354. (d)
Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 779-831. (e)
Curran, D. P.; Fevig, T. L.; J asperse, C. P.; Totleben, M. J . Synlett
1992, 943-961.
(1) (a) Wilson, B. J .; Wilson, C. H.; Hayes, A. W. Nature 1968, 220,
77. (b) de J esus, A. E.; Steyn, P. S.; van Heerrden, F. R.; Vleggar, R.;
Wessels, P. L.; Hull, W. E. J . Chem. Soc., Perkin Trans. 1 1983, 1857-
1861.
(2) For the first total synthesis of penitrem D, see: (a) Smith, A.
B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J . Am. Chem. Soc. 2000,
122, 11254-11255. (b) Kanoh, N.; Smith, A. B., III; Ishiyama, H.;
Minakawa, N.; Rainier, J . D.; Hartz, R. A.; Cho, Y. S.; Cui, H.; Moser,
W. H. J . Am. Chem. Soc. 2003, 125, 8228-8237.
(7) The reaction was carried out under “Barbier conditions”: addi-
tion of halide and ketone together in THF to a solution of SmI2‚4HMPA.
See: Curran, D. P.; Totleben, M. J . J . Am. Chem. Soc. 1992, 114, 6050-
6058.
(8) For example, the ketone group of cyclobutanones has often been
used in radical cyclization reactions: Dowd, P.; Zhang, W. Chem. Rev.
1993, 93, 2091-2115. Cyclizations to methylene cyclobutanes are also
known: Zhang, W.; Dowd, P. Tetrahedron Lett. 1995, 36, 8539-8542.
(9) Examples of radical additions to cyclobutenes: (a) Ferjancˇic´, Z.;
Cˇ ekovic´, Z.; Saicˇic´, R. N. Tetrahedron Lett. 2000, 41, 2979-2982. (b)
Campbell, E. F.; Park, A. K.; Kinney, W. A.; Fengl, R. W.; Liebeskind,
L. S. J . Org. Chem. 1995, 60, 1470-1472. (c) Legrand, N.; Quiclet-
Sire, B.; Zard, S. Z. Tetrahedron Lett. 2000, 41, 9815-9818. (d) Chen,
X.-P.; Sufi, B. A.; Padias, A. B.; Hall, H. K., J r. Macromolecules 2002,
35, 4277-4281.
(3) For a recent communication of our synthetic work in this area,
see: Rivkin, A.; Nagashima, T.; Curran, D. P. Org. Lett. 2003, 5, 419-
422.
(4) We use here the “radical/polar crossover” terminology of Murphy,
but such reactions are also called by other names such as “cascade
radical/ionic reactions”. Bashir, N.; Patro, B.; Murphy, J . A. Advances
In Free Radical Chemistry; Zard, S. Z., Ed.; J ai Press: Stamford, CT,
1999; Vol. 2, pp 123-150.
(5) (a) Nagashima, T. Ph.D. Thesis, University of Pittsburgh, 1999.
(b) Rivkin, A. Ph.D. Thesis, University of Pittsburgh, 2001.
10.1021/jo049873s CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/28/2004
J . Org. Chem. 2004, 69, 3719-3725
3719

Rivkin et al.
the exo-methylene 13, followed by formation of the phenyl
selenide 18 and final selenoxide elimination.
The nitrile precursor 29 was synthesized starting from
the chlorocyclobutane 19. This was transformed into 20
by reaction with sodium phenylselenide in refluxing
DME. Tosylation of the primary alcohol in 20 gave 21,
which was reacted with potassium cyanide to produce the
desired cyclobutane 22. An alkylation reaction between
the nitrile 22 and 2-iodo-1-iodomethyl-3-methyl-benzene,
followed by selenoxide elimination in 23 provided the
desired nitrile precursor 29 as a 1:1 mixture of dia-
stereoisomers (Scheme 1).
Ra d ica l Cycliza tion s a n d Ra d ica l/P ola r Cr oss-
over Rea ction s. To test the feasibility of the radical
cyclizations, reactions of the substrates 24-29 were first
conducted using the tributyltin hydride method.12 In a
typical experiment, the cyclization of precursor 1 was
performed in refluxing benzene (80 °C) in the presence
of AIBN (0.2 equiv). Purification by flash column chro-
matography allowed the separation of both the cyclized
and reduced compounds when the reaction was per-
formed with precursors 24-26 and syn-27 (entries 1-4,
Table 1). With anti-27, 28, and 29 the cyclized and
reduced products could not be separated preparatively,
1
so the ratios were determined by H NMR spectroscopic
analysis of the mixtures.
The effect of different substituents on the rates of
cyclization was determined by standard competition
kinetics. In a typical sequence of experiments, the cy-
clization of precursor 1 was performed under the condi-
tions described above at 3-5 different concentrations of
tributyltin hydride (Figure 3).12e The ratios of the cyclized
(31) to reduced products (30) (kC/kH) were determined
either by GC or 1H NMR spectroscopic analysis of the
crude reaction products. Finally, the corresponding rate
constant (kc) of the different cyclization reactions were
calculated by using the recommended rate constant for
reduction of an aryl radical by Bu3SnH at 80 °C in
benzene (kH ) 1.0 × 109 M-1s-1).12g
F IGURE 2. Tandem radical/polar reaction.
of intramolecular additions of radicals to cyclobutenes.
Herein, we provide the full account of our investigations
in this area, including rate constant determination and
experimental evidence for the stereochemical outcome of
these processes.3
Resu lts a n d Discu ssion
Syn th esis of P r ecu r sor s. The study started with the
synthesis of substrates 24-29 with different R1, R2, and
R3 groups to prove the generality of the approach, keeping
in mind that the R1, R2 groups should be converted into
the exo-methylene group present in the penitrems. Start-
ing from the readily available ketones 7 or 8,10 ketals 24-
26, silyl ether 27, and exo-methylene substrate 28 were
synthesized by a common strategy that involved a selen-
oxide elimination in the final step. The synthesis of the
precursors 24-26 started with the ketalization of 7 or 8
with the appropriate diols. Subsequent phenylselenide
formation of intermediates 9-11 led to compounds 14-
16 that underwent selenoxide elimination to give the
desired ketal precursors 24-26.
The synthesis of the silyl ether 27 involved reduction
of the ketone 7, followed by phenyl selenide formation to
give secondary alcohol 12. Protection of the alcohol as
the silyl ether 17 and finally selenoxide elimination
allowed access to both diastereoisomers of the silyl ether
substrate 27.11 In the case of the exo-methylene substrate
28, the synthesis involved conversion of the ketone 7 to
The results of these experiments are summarized in
Table 1. The intramolecular radical cyclization of an aryl
radical into a cyclobutene is a facile process with isolated
yields of cyclized products ranging from 49% to 90%.
Estimated cyclization rate constants, kc, fall in a narrow
range of 2.8-6.5 × 108 s-1. Cyclizations of the dioxane
ketal precursor and the lower dioxolane homologue
occurred in similar yields (entries 1 and 2; 84% and
82%), whereas the o-methyl-substituted analogue gave
a slightly lower yield (entry 3, 59%).13 This suggests that
the size of the ketal and presences of ortho substituents
have little influence on the cyclization process. In the
cases of the diastereomeric alcohols (entries 4 and 5), the
(12) (a) Newcomb, M. Tetrahedron 1993, 49, 1151-1176. (b) Beck-
with, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41, 3925-3941. (c)
Beckwith, A. L. J .; Zimmermann, J . J . Org. Chem. 1991, 56, 5791-
5796. (d) J ohnston, L. J .; Lusztyk, J .; Wayner, D. D. M.; Abeywickrema,
A. N.; Beckwith, A. L. J .; Scaiano, J . C.; Ingold, K. U. J . Am. Chem.
Soc. 1985, 107, 4594-4596. (e) Abeywickrema, A. N.; Beckwith, A. L.
J . J . Chem. Soc., Chem. Commun. 1986, 464-465. (f) Beckwith, A. L.
J .; Gara, W. B. J . Chem. Soc., Perkin Trans. 2 1975, 795-802. (g)
Garden, S. J .; Avila, D. V.; Beckwith, A. L. J .; Bowry, V. W.; Ingold,
K. U.; Lusztyk, J . J . Org. Chem. 1996, 61, 805-809. (h) Beckwith, A.
L. J .; Gerba, S. Aust. J . Chem. 1992, 45, 289-308.
(10) A detailed description of the syntheses can be found in Sup-
porting Information. See also Supporting Information of ref 3.
(11) The relative stereochemistry of the syn-27 and anti-27 precur-
sors was assigned on the basis of the relative stereochemistry of the
corresponding cyclized products 38 and 40 (these were assigned by
analysis of the coupling constant between the secondary benzylic
hydrogens and the neighboring tertiary silyl ether hydrogen).
(13) For a discussion of the influence of ortho substituents in radical
mediated cyclizations, see: Curran, D. P.; Fairweather, N. J . Org.
Chem. 2003, 68, 2972-2974.
3720 J . Org. Chem., Vol. 69, No. 11, 2004

BCD Ring System of Penitrem D
SCHEME 1a
a
Reagents and conditions: (a) Dean-Stark, HOCH2CH2OH, PTSA, PhH; (b) PhSeNa, DME, reflux; (c) (1) m-CPBA, CH2Cl2, -78 to 25
°C, (2) Et2NH, CH2Cl2, reflux; (d) (1) NaBH4, MeOH, rt, (2) PhSeNa, DME, reflux; (e) TBSCl, DMF, imidazole; (f) (1) m-CPBA, CH2Cl2,
(2) Et2NH, 1,2-dichloroethane, 14 h, reflux; (g) Tebbe reagent, toluene; (h) (1) m-CPBA, CH2Cl2, -78 °C, (2) CHCl3, Et2NH, reflux; (i)
TsCl, Et3N, DMAP, CH2Cl2; (j) KCN, DMSO, 80 °C; (k) NaHMDS, -78 °C, 22, 90 min, then 2-iodo-1-iodomethyl-3-methyl-benzene, HMPA,
-78 to 25 °C; (l) (1) m-CPBA, CH2Cl2, -78 to 25 °C, (2) Et2NH, 1,2-dichloroethane, 5 h, reflux.
Having established the viability of the radical cycliza-
tions of the substrates 24-29, we investigated radical
reactions of these substrates with tert-butyl alcohol
promoted by samarium diiodide and HMPA. The results
of these studies are also shown in Table 1. In a typical
reaction, the cyclization precursor 24 (entry 1, Table 1)
was added to a solution of SmI2 (3 equiv), HMPA (12
equiv), and tert-butyl alcohol in THF at 25 °C, and the
resulting reaction mixture was stirred for 30 min. Aque-
ous workup followed by flash column chromatography
provided the cyclized product 32 in 73% yield along with
the reduced product 33 in 16% yield. The directly reduced
product most likely results from hydrogen abstraction by
the intermediate aryl radical from the medium, although
this has not been demonstrated experimentally.6c The
F IGURE 3. Competition kinetics for aryl radical cyclization.
trends of yields employing this cyclization method were
similar to those obtained with tributyltin hydride, which
suggests that the cyclization is independent of the
method employed to generate the aryl radical.
exo-methylene radical (entry 6), and the nitriles (entry
7), we observe somewhat lower cyclization rate constants
and the combined yields of the corresponding cyclized and
With the success of the SmI2-mediated reactions with
tert-butyl alcohol established, we then tested the viability
of the tandem radical/polar crossover reactions with
acetone. In a typical experiment, a solution of substrate
24 (entry 1, Table 2) and acetone in THF was added to a
solution of SmI2 (4 equiv) and HMPA (16 equiv) in THF
reduced products range between 76% and 90%. These
studies establish the generality of the cyclization reaction
with different substituents R1, R2, and R3 and suggest
that ketal (and perhaps other quaternary) substituents
are better suited than the protected hydroxy, methylene,
or nitrile groups for the reaction.
J . Org. Chem, Vol. 69, No. 11, 2004 3721

Rivkin et al.
TABLE 1. Bu 3Sn H- a n d Sm I2/t-Bu OH-Med ia ted Cycliza tion Rea ction s
a
b
d
Reaction carried out at 0.1 M. Reaction carried out at 0.2 M. c Ratio determined by 1H NMR. Mixture (1:1) of diastereoisomers.
e Products inseparable, ratio determined on mixture.
3722 J . Org. Chem., Vol. 69, No. 11, 2004

BCD Ring System of Penitrem D
TABLE 2. Sm I2-Med ia ted Cycliza tion Rea ction s w ith Aceton e
a
b
Inseparable, ratio determined by 1H NMR. Mixture (1:1) of diastereoisomers.
at 25 °C and the resulting reaction mixture was stirred
for 30 min. Aqueous workup followed by flash column
chromatography provided the desired products in yields
shown in Table 2.
The radical/polar crossover reactions with acetone
trapping proceed in acceptable yields with different R1
and R2 substituents. In particular, we observed that the
yields of the corresponding products of the ketal-bearing
substrates 24-26 (entries 1-3, 59-60%) were similar,
which reinforced the idea of that there was very little
effect of the ring size of the ketal or the o-methyl group
on the cyclization reaction. The diastereomeric alcohols
syn-27 and anti-27 (entries 4 and 5) cyclized to give the
corresponding products 49 and 50 in 40% and 45%
J . Org. Chem, Vol. 69, No. 11, 2004 3723

Rivkin et al.
SCHEME 2a
a
Reagents and conditions: (a) (i) SmI2, HMPA, acetone, (ii) flash chromatography; (b) DibalH, DCM, -78 to 25 °C, 5 h; (c) NaBH4,
MeOH, 2 h.
isolated yields, respectively.14 Reductive cyclization of the
exo-methylene substrate 28 (entry 6, Table 2) provided
the hydroxyalkylated tricycle 51 in 41% isolated yield,
and the nitrile precursor 29 (entry 7, Table 2) yielded a
1:1 mixture of two diastereoisomers 52 that were sepa-
rated by column chromatography. In all cases, two side
products were formed, which were reduced products (13-
38%) and small amounts (2-5%) of the products from
successful radical cyclization but failed polar addition.
Yields of the directly reduced products were in line with
expectations from the Bu3SnH and SmI2/tert-butyl alcohol
experiments.
The cyclizations are expected to give the corresponding
cis ring fusion products based on previous observations
in the formation of bicycles of different ring sizes by
radical cyclizations.15 The exo addition of acetone was
supported by the observation of a strong cross-peak
between one of the methyl groups and the adjacent ring
fusion hydrogen in a 2D NOE NMR experiment.16 Fur-
ther evidence was obtained when the two separated
diastereoisomers of the nitrile 52 were independently
reduced to the corresponding diols 54 and 56. These
transformations were performed by a two-step proce-
dure employing DibalH in dichloromethane to give alde-
hydes 53 and 55 (Scheme 2), followed by treatment with
NaBH4 in methanol that gave the corresponding diols 54
and 56.
The relative configuration of 54 was confirmed by X-ray
crystallography, and that of the alcohol 56 was estab-
lished by comparison of its spectroscopic properties with
a closely related intermediate (57) reported by Smith and
co-workers (Figure 4).2 Notably, 56 exhibited 1H NMR
(both multiplicity and chemical shift) and 13C NMR data
in the upfield region almost identical to those of the diol
57. These spectra only differed in the signals correspond-
ing to the substitution pattern of the aromatic ring.
F IGURE 4. Establishment of configurations by crystal-
lography of 54 and comparison of 56 to known 57.
P a lla d iu m -Ca t a lyzed Cycliza t ion s. Palladium-
catalyzed cyclizations have been frequently applied to-
ward the synthesis of complex polycyclic ring systems.17
Since we were unable to locate any examples of pal-
ladium(0)-mediated cyclizations of cyclobutene, we de-
cided to test this idea using substrates 24-29. The
results of these studies are shown in Table 3. In a typical
experiment, the substrate 24 (entry 1, Table 3) was added
to a solution of Pd(PPh3)4 (20% mol) and triethylamine
in acetonitrile, and the resulting mixture was refluxed
for 12 h. Aqueous workup followed by flash column
chromatography provided the tricycle 58 in 84% yield.
(14) Configurations were tentatively assigned on the basis of the
observation of a trans-diaxial coupling constant (11 Hz) between the
proton adjacent to the OTBS group and one of the benzylic methylene
protons in anti-27. Both modeling and the crystal structure of 54
indicated a dihedral angle of close to 180° in this isomer.
(15) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH:
Weinheim, 1996.
(17) Examples of Heck cyclizations: (a) Zhang, Y.; O’Conner, B.;
Negishi, E. J . Org. Chem. 1988, 53, 5590-5592. (b) Larock, R. C.; Song,
H.; Baker, B. E.; Gong, W. H. Tetrahedron Lett. 1988, 24, 2919-2922.
(c) J in, Z.; Fuchs, P. L. Tetrahedron Lett. 1993, 33, 5205-5208. (d)
Negishi, E.; Zhang, Y.; O’Conner, B. Tetrahedron Lett. 1988, 24, 2915-
2918. (e) Grigg, R.; Santhakumar, V.; Sridharan, V. Tetrahedron Lett.
1993, 34, 3163-3164. (f) Torii, S.; Okumoto, H.; Ozaki, H.; Nakayasu,
S.; Tadokoro, T.; Kotani, T. Tetrahedron Lett. 1992, 24, 3499-
3502.
(16) Experiment performed in the cyclized products 48 and 50.
3724 J . Org. Chem., Vol. 69, No. 11, 2004

BCD Ring System of Penitrem D
TABLE 3. P a lla d iu m (0)-Med ia ted Cycliza tion Rea ction s
Cyclization of the other substrates occurred in compa-
rable yields. In contrast to radical cyclization trends, the
similarity of the yields of the Heck products suggests that
variation of the substitution had very little effect on the
reaction. This result can be attributed to the lack of side
reaction pathways present in the palladium(0)-mediated
cyclizations of the substrates.
Con clu sion s
In summary, we have shown that cyclization reactions
of derivatives of 1-(2-cyclobutenyl)-2-(2-iodoaryl)etha-
nones are efficiently promoted by tributyltin hydride,
samarium diiodide, and palladium(0) to provide the
target cyclized products in moderate to high yields. Rate
constant studies with tributyltin hydride established the
success and the broad scope of radical cyclizations to
cyclobutenes. This reaction tolerates several substituents
at the key carbon atom that bears a exo-methylene group
in the penitrems. Radical/polar crossover reactions of
derivatives of 1-(2-cyclobutenyl)-2-(2-iodoaryl)ethanones
with acetone or tert-butyl alcohol promoted by samarium
diiodide have been used to construct the BCD ring system
of the penitrems. Furthermore, we have described the
first examples of palladium(0)-mediated cyclizations to
cyclobutenes. This reaction may prove to be useful for
syntheses of fused cyclobutene rings in complex ring
systems. Radical and Pd-catalyzed cyclizations to cyclo-
butenes provide a powerful strategy for the synthesis of
fused cyclobutane and cylobutene rings, and this encour-
ages further development of such strategies toward the
penitrem class of natural products.
Ack n ow led gm en t. We thank the National Institute
of Health for funding this work. We also thank Dr. Fu-
Tyan Lin (NMR facilities), Dr. Kasi Somayajula (mass
spectrometry facilities), and Dr. Steven Geib (X-ray
measurements) for their assistance. Alexey Rivkin
thanks the Bayer Corporation for a Bayer graduate
fellowship.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and characterization for syntheses of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
b
Mixture (1:1) of diastereoisomers. Mixture (1:1) of diastereo-
isomers, compounds separated by column chromatography.
J O049873S
J . Org. Chem, Vol. 69, No. 11, 2004 3725