Skeletal diversity through radical cyclization of tetrahydropyridine scaffolds

Article abstract of DOI:10.1021/ol701722z

Suitably functionalized tetrahydropyridines (methyl pipecolates) have been used as conformationally biased templates for radical cyclizations to access benzoisoquinuclidines and linearly fused indenopiperidines. Variation of skeletal types is determined b

Full text of DOI:10.1021/ol701722z

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3849-3852
Skeletal Diversity through Radical
Cyclization of Tetrahydropyridine
Scaffolds
Sivaraman Dandapani, Mihai Duduta, James S. Panek,* and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
panek@bu.edu; porco@bu.edu
Received July 19, 2007
ABSTRACT
Suitably functionalized tetrahydropyridines (methyl pipecolates) have been used as conformationally biased templates for radical cyclizations
to access benzoisoquinuclidines and linearly fused indenopiperidines. Variation of skeletal types is determined by location of a radical-
initiating element.
Diversity generation by systematic variation of substituents
around a given scaffold has remained central to library
synthesis.1 We reasoned that the emerging area of skeletal
diversity2 can potentially benefit by identifying suitable
reactive intermediates that have broad yet predictable
reactivity patterns in complex molecular frameworks. An
underdeveloped approach to skeletal diversity involves design
and synthesis of conformationally biased scaffolds for radical
cyclizations. Generation, reactivity, and stereoselectivity of
free radical intermediates have been well-studied,3 and
application of radical cyclization continues to attract attention
in target-oriented synthesis.3d,f,4 However, applications of
radical chemistry to diversity-oriented synthesis5 and genera-
tion of skeletal diversity remain underdeveloped. In this paper,
we illustrate how the selection of reaction partners for [4
+2 ] annulation assembles pipecolate templates as radical
cyclization precursors while strategically positioning radical-
initiating sites at different locations. A stereroselective
(1) (a) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997.
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in Organic Synthesis, Volume 2: Applications; Renuad, P., Sibi, M P., Eds.;
Wiley-VCH: Weinheim, 2001. (e) Gansauer, A., Ed. Radicals in Synthesis
I: Methods and Mechanisms. In Top. Curr. Chem. 2006, 263, 1-199. (f)
Gansauer, A., Ed. Radicals in Synthesis II: Complex Molecules. In Top.
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10.1021/ol701722z CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/22/2007

alkylation of the pipecolate scaffold is also used to install
radical-initiating and -terminating sites.
Table 1. Alkylation of Tetrahydropyridinesa,b
We have previously reported stereoselective syntheses of
both 2,6-cis- and 2,6-trans-substituted tetrahydropyridines
employing intramolecular crotylation of imines derived from
condensation of enantioenriched aminosilanes with alde-
hydes.6 We anticipated that placement of a radical initiating
site at different positions of a tetrahydropyridine scaffold 1
may enable different modes of radical additions to the
C3-C4 double bond to generate novel alkaloidal structures
(Scheme 1).7 For example, in substrate 1 the 2-bromophenyl
radical initiator element is placed at C6 while 3 has the
2-bromophenyl unit appended through the C2 position.
Scheme 1. Skeletal Diversity from Tetrahydropyridine
Scaffolds
Different radical cyclization pathways of substrates 1 and 2
should thus generate complementary cyclized products 3 and
4, respectively. It is also noteworthy that the new scaffolds
are produced by a common mode of reaction (i.e., radical
cyclization), so that there is no need to modify the reacting
subunits (2-bromophenyl and the C-C double bond) to
access different skeletal frameworks.
a LiHMDS (2 equiv), RX (5 equiv), HMPA (5.0 equiv), THF, -78 to 0
°C, 5 h. b Product was isolated as a single diastereomer. c Reported yield
after silica gel chromatography.
Preparation of radical cyclization substrates was carried
out by alkylation of the dienolates species derived from
tetrahydropyridine 1. Treatment of 1 with LiHMDS and
further reaction of the resulting dienolate with an alkyl halide
provided the R-alkylation products with high diastereose-
lectivity.8 Results of alkylation experiments are summarized
in Table 1. For example, alkylation of 1 with methyl iodide
resulted in the regio- and diastereoselective alkylation to
afford product 15 in 85% isolated yield. In a similar manner,
the o-bromophenyl-substituted tetrahydropyridine 1 was
alkylated with propargyl, 3-methylpropargyl, allyl, and a
range of substituted allyl halides (entries 2-7) in moderate
to high yields. A 2-alkynylbenzyl group was also installed
at the C2 position of ent-1 using this alkylation procedure
(entry 8). Tetrahydropyridine 5 bearing a phenyl group at
C6 was also efficiently alkylated with both 2-bromobenzyl
and allyl bromides (entries 9 and 10), respectively. In all
cases examined, a single diastereomer was obtained.
Stereochemical assignment of the newly formed quaternary
center was carried out using NOE measurements of product
15 which indicated that the two methyl groups are cis to
each other.8 The calculated ground-state structure of 15 and
the observed NOE data are depicted in Figure 1A.9 We
rationalize the observed selectivity based on the calculated9
structure of a lithium enolate derived from 1 wherein the
electrophile approaches the enolate in a pseudoequatorial
orientation (Figure 1B). As is evident from the model, axial
approach of the electrophile would encounter severe steric
interactions with the C6 aryl group.
A number of precursors were prepared with the 2-bro-
mophenyl subunit at two different locations on the tetra-
hydropyridine core. We then investigated the feasibility of
radical cyclizations to assemble novel frameworks such as
(6) (a) Huang, H.; Spande, T. F.; Panek, J. S. J. Am. Chem. Soc. 2003,
125, 626. (b) Dandapani, S.; Lan, P.; Beeler, A. B.; Beischel, S.; Abbas,
A.; Roth, B. R.; Porco, J. A., Jr.; Panek, J. S. J. Org. Chem. 2006, 71,
8934.
(7) (a) Gan, Z.; Reddy, P. T.; Quevillon, S.; Couve-Bonnaire, S.; Arya,
P. Angew. Chem., Int. Ed. 2005, 44, 1366. (b) Reddy, P. T.; Quevillon, S.;
Gan, Z.; Forbes, N.; Leek, D. M.; Arya, P. J. Comb. Chem. 2006, 8, 856.
(8) See the Supporting Information for complete experimental details.
(9) Conformational analysis was carried out using a Molecular Operating
Environment (MOE) (version 2006.08) stochastic search.
3850
Org. Lett., Vol. 9, No. 19, 2007

71% yield with the use of tris(trimethylsilyl)silane10 and
AIBN (entry 3). Under these modified conditions 28, the
C2 epimer of 1, also gave the corresponding benzoisoqui-
nuclidine 29 in 77% isolated yield (entry 4).
A mechanistic analysis and proposal for the high levels
of regioselectivity leading to the formation of benzoisoqui-
nuclidines is provided in Scheme 2. Aryl radical 30 can
Scheme 2. Mechanistic Analysis for Regioselectivity in
Radical Cyclization of 21
Figure 1. (A) Calculated ground-state structure of 15 with observed
NOE indicated with arrow. (B) Proposed transition-state model for
the stereochemical outcome of alkylation.
benzoisoquinuclidines and indenopiperidines. Treatment of
23 with tributyltin hydride in the presence of a catalytic
amount of AIBN (80 °C) cleanly afforded the indenopip-
eridine 25 in 81% isolated yield (Table 2, entry 1). When
Table 2. Results of Radical Cyclizations with a Single C-C
Bond Formation
potentially partition via 5-exo-trig and 6-endo-trig pathways
to intermediates 31 and 32, respectively (Scheme 2). Ac-
cording to literature precedent,3,11 radical intermediate 31
should be formed in greater amounts as 5-exo-trig cyclization
is kinetically favored over the 6-endo-trig process. However,
radicals 31 and 32 may equilibrate through the cyclopropyl-
carbinyl radical 33 by a neophyl rearrangement12 ultimately
favoring the more stable [2.2.2]bicyclo radical 32. In
addition, the rate of reduction of 31 by tributyltin hydride
will also be significantly lower compared to that of 32 due
a AIBN, Bu3SnH, 80 °C, 4 h, benzene. b AIBN, (Me3Si)3SiH 80 °C, 4
h, benzene.
the methylated tetrahydropyridine 21 was subjected to these
reaction conditions, benzoisoquinuclidine 26 was isolated as
a single product in 89% yield (entry 2), illustrating the
consequence of positional variation of the radical initiating
site. Tetrahydropyridine 1 when subjected to radical cycliza-
tion with tributyltin hydride, afforded the benzoisoquinucli-
dine 27 with a small amount of an unidentified byproduct.
After screening several different initiators and reducing
agents, we found that 1 could be cleanly converted to 27 in
(10) Kanabus-Kaminska, J. M.; Hawari, J. A.; Griller, D.; Chatgilialoglu,
C. J. Am. Chem. Soc. 1987, 109, 5267.
(11) Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939 (a) Curran,
D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140. (b) Yadav, V.; Fallis,
A. G. Tetrahedron Lett. 1989, 30, 3283.
(12) (a) Beckwith, L, J.; O’Shea, D. M. Tetrahedron Lett. 1986, 27, 4525.
(b) Stork, G.; Mook, R., Jr. Tetrahedron Lett. 1986, 27, 4529. (c) Ishibashi,
H.; Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem. 2000, 65,
9022. (d) Toyota, M.; Yokota, M.; Ihara, M. J. Am. Chem. Soc. 2001, 123,
1856.
Org. Lett., Vol. 9, No. 19, 2007
3851

to steric hindrance of the radical center in 31 by the adjacent
quaternary center.13
Scheme 4. Tandem Radical Cyclizations with Two C-C
Bond Formations
To extend the utility of these scaffolds to access additional
structural frameworks, indenopiperidine 25 was deacylated
using methanolic KOH. The resulting amino acid was
converted to the tetracyclic hydantoin 35 in 62% isolated
yield over the two steps (Scheme 3).
Scheme 3. Deprotection and Complex Hydantoin Formation
The high “6-endo-trig” selectivity observed for cyclization
of 21 suggested that the intermediate radical formed in these
reactions may be subjected to a second cyclization if a
suitable radical acceptor is located at the C2 position of the
tetrahydropyridine. Accordingly, treatment of the allylated
tetrahydropyridine 17 with tris(trimethylsilyl)silane and
AIBN in benzene at 80 °C resulted in tandem cyclization to
produce scaffold 36 as a single diastereomer at C7 in 65%
isolated yield (Scheme 4). The stereochemical outcome of
this reaction may be rationalized by the Beckwith-Houk
transition-state model14 (inset, Scheme 4) where the exocyclic
olefin is oriented away from the existing methyl group. We
also designed a two-step sequence to access the C7 epimer
of 36. Tandem radical cyclization of the propargylated
tetrahydropyridine 16 gave 37 in 76% yield, which was
followed by hydrogenation of the exocyclic double bond
using Adam’s catalyst, which cleanly afforded the complex
scaffold 38 as a single diastereomer bearing an epimeric
relationship to 36 at C7.
duce both radical initiation and termination sites to the
scaffolds for subsequent cyclizations. Indenopiperidines and
benzoisoquinuclidines were readily accessed by radical
cyclizations that form a single C-C bond. Complex ben-
zoisoquinuclidines were also accessed by tandem radical
cyclizations with attendant formation of two C-C bonds.
Further studies, including library expansion and biological
evaluation of the novel chemotypes, are currently under
investigation and will be reported in due course.
Acknowledgment. Financial support from the NIGMS
CMLD initiative (P50 GM067041) is gratefully acknowl-
edged. We thank Professors John Snyder and Scott Schaus
and Dr. Aaron Beeler (Boston University) for helpful
discussions and Mr. Christopher Singleton and Mr. Joshua
Giguere (Boston University) for NMR assistance.
In summary, radical cyclizations of tetrahydropyridine
scaffolds have been used to access diverse skeletal frame-
works. Stereoselective alkylations were employed to intro-
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For a similar analysis of differences in rates of reduction based on
steric encumbrance around the radical center, see ref 12c.
(14) (a) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. (b) Beckwith,
A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925. (c) Spellmeyer, D.
C.; Houk, K. N. J. Org. Chem. 1987, 52, 959. (d) Curran, D. P.; Porter, N.
A.; Giese, B. Stereochemistry of Radical Reactions; VCH: Weinheim, 1996.
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