Enantioselective cyclization of alkene radical cations

Article abstract of DOI:10.1021/ol035564x

(Matrix Presented) Enantiomerically enriched β-(diphenylphosphatoxy) nitroalkanes undergo radical ionic fragmentation, induced by tributyltin hydride and AIBN in benzene at reflux, to give alkene radical cations in contact radical ion pairs. These contact

Full text of DOI:10.1021/ol035564x

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3767-3769
Enantioselective Cyclization of Alkene
Radical Cations
David Crich,* Michio Shirai, and Sochanchingwung Rumthao
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received August 20, 2003
ABSTRACT
Enantiomerically enriched
in benzene at reflux, to give alkene radical cations in contact radical ion pairs. These contact ion pairs are trapped intramolecularly by amines
to give pyrrolidines and piperidines with significant enantioselectivity ( 60% ee), indicative of cyclization competing effectively with equilibration
â-(diphenylphosphatoxy)nitroalkanes undergo radical ionic fragmentation, induced by tributyltin hydride and AIBN
∼
within the ion pairs. Use of an intramolecular N-propargylamine as a nucleophile provides an enantiomerically enriched pyrrolizidine skeleton
via a tandem polar/radical crossover sequence.
Alkene radical cations may be advantageously generated
under reducing conditions by the radical ionic fragmentation
of â-(phosphatoxy)alkyl radicals.1-3 In nonpolar solvents,
the contact radical ion pair generated on fragmentation
undergoes rapid recombination to provide either a rearranged4
or the initial5 radical depending on the substituent pattern.
Both of these processes take place with a high degree of
retention of configuration at phosphorus, indicative of the
short lifetimes of the contact radical ion pair. The incorpora-
tion of suitable nucleophiles, particularly allylamines, in the
system enables trapping of the alkene radical cation in
tandem polar/radical crossover reactions leading to the
formation of numerous alkaloid skeletons and other hetero-
cyclic systems.6 If nucleophilic trapping of the alkene radical
cation is to compete effectively with formation of the
rearranged radical in nonpolar solvents, then it must neces-
sarily take place at the level of the initial contact radical ion
pair. This in turn implies a high degree of organization in
the trapping reaction and raises the possibility of stereo-
controlled additions, even though the alkene radical cation
itself is planar and devoid of chirality. Indeed, we have
observed high diastereoselectivity in the cyclization of a
series of methyl substituted â-(phosphatoxy)alkyl radicals
(1) (a) Newcomb, M.; Horner, J. H.; Whitted, P. O.; Crich, D.; Huang,
X.; Yao, Q.; Zipse, H. J. Am. Chem. Soc. 1999, 121, 10685-10694. (b)
Whitted, P. O.; Horner, J. H.; Newcomb, M.; Huang, X.; Crich, D. Org.
Lett. 1999, 1, 153-156. (c) Newcomb, M.; Miranda, N.; Huang, X.; Crich,
D. J. Am. Chem. Soc. 2000, 122, 6128-6129.
(2) â-(Sulfonatoxy)alkyl radicals behave analogously: (a) Koltzenburg,
G.; Behrens, G.; Schulte-Frohlinde, D. J. Am. Chem. Soc. 1982, 104, 7311-
7312. (b) Crich, D.; Filzen, G. F. Tetrahedron Lett. 1993, 34, 3225-3226.
(c) Taxil, E.; Bagnol, L.; Horner, J. H. Newcomb, M. Org. Lett. 2003, 5,
827-830. (d). Lancelot, S. F.; Cozens, F. L.; Schepp, N. P. Org. Biomol.
Chem. 2003, 1, 1972-1979.
(3) For classical oxidative approaches to alkene radical cations from
alkenes themselves, see: (a) Hintz, S.; Heidbreder, A.; Mattay, J. In Topics
in Current Chem; Mattay, J., Ed.; Springer: Berlin, 1996; Vol. 177, p 77.
(b) Bauld, N. L.; Bellville, D. J.; Harirchian, B.; Lorenz, K. T.; Pabon, R.
A.; Reynolds, D. W.; Wirth, D. D.; Chiou, H.-S.; Marsh, B. K. Acc. Chem.
Res. 1987, 20, 371-378. (c) Schmittel, M.; Burghart, A. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2550-2589.
(4) (a) Beckwith, A. L. J.; Crich, D.; Duggan, P. J.; Yao, Q. Chem. ReV.
1997, 97, 3273-3312. (b) Crich, D. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 188-
206. (c) Crich, D.; Quintero-Cortes, L.; Sartillo-Piscil, F.; Wink, D. J. Org.
Chem. 2002, 67, 3360-3364.
(5) Crich, D.; Huang, X. J. Am. Chem. Soc. 2001, 123, 9239-9245.
(6) (a) Crich, D.; Ranganathan, K.; Huang, H. Org. Lett. 2001, 3, 1917-
1920. (b) Crich, D.; Neelamkavil, S. Org. Lett. 2002, 4, 2573-2575. (c)
Crich, D.; Ranganathan, K.; Neelamkavil, S.; Huang, X. J. Am. Chem. Soc.
2003, 125, 7942-7947. (d) Crich, D.; Huang, X.; Newcomb, M. J. Org.
Chem. 2000, 65, 523-529. (e) Sartillo-Piscil, F.; Vargas, M.; Anaya de
Parrodi, C.; Quintero, L. Tetrahedron Lett. 2003, 44, 3919-3921.
10.1021/ol035564x CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/10/2003

to pyrrolidines, which is consistent with this hypothesis.7
These cyclizations were rationalized in terms of chairlike
transition states, with the maximum number of pseudoequa-
torial substitutents, in which the nucleophilic amine attacks
the alkene radical cation on the opposite face to the phosphate
anion (Scheme 1).
the Corey oxazaborolidine reduction of R,R-disubstituted-
R-nitroketones developed in this laboratory.8 The absolute
configurations of all nitro alcohols prepared were assigned
following the standard Corey model,9 as rigorously estab-
lished previously.8,10 The synthesis of pyrrolidine and piper-
idine precursors 11 and 12 (Scheme 2) was otherwise
straightforward and proceeded from readily available materi-
als.
Treatment of 11 with tributyltin hydride and AIBN in
benzene at reflux resulted in the isolation of pyrrolidine 13
in 43% yield and 61% ee (Table 1). Taking into account the
85% ee of the substrate, it is readily calculated that 13 with
71% ee would be obtained if enantiomerically pure 11 were
used in this cyclization. The absolute configuration of 13
was assigned following hydrogenolysis and reaction with
Scheme 1. Diastereoselective Formation of Pyrrolidines
In this communication, we show, with enantiomerically
enriched â-nitrophosphate radical cation precursors, that the
concept may be extended to enantiomerically controlled
cyclizations of alkene radical cations, and that the confor-
mational influence of the methyl groups in Scheme 1 was
not a major stereodetermining factor. Additionally, we show
that the sequence is readily extended to the formation of
piperidines, i.e., that stereocontrol is not significantly eroded
by the formation of six- rather than five-membered rings,
and to tandem polar/radical crossover sequences.
Table 1. Enantioselective Alkene Radical Cation Cyclizations
As previously, the precursors of choice to the â-(phos-
phatoxy)alkyl radicals were the readily assembled, stable
tertiary â-nitrophosphates.6,7 This required the asymmetric
synthesis of these substances, for which we have employed
Scheme 2. Synthesis of Enantiomerically Enriched Radical
Precursors
a Actual ee (ee predicated on enantiomerically pure substrate).
3768
Org. Lett., Vol. 5, No. 20, 2003

tosyl chloride when (S)-(-)-2-isopropyl-1-tosylpyrrolidine
was obtained, whose specific rotation conformed to the
literature value.11 The absolute configuration of 13 is
consistent with the model set out in Scheme 3, in which
of the carbamate in the standard manner, this conveniently
afforded substrate 17 for a tandem polar radical crossover
reaction6 with the formation of pyrrolizidine 18 (Table 1).
Finally, we turned our attention to alcohols as nucleophile
and the formation of tetrahydrofurans. Substrate 19 was
prepared as described in Supporting Information, with the
key step being oxazaboroline-catalyzed reduction of a nitro
ketone much like that in Scheme 2, and subjected to tin
hydride reduction under the standard conditions. Tetra-
hydrofuran 20 was isolated in 25% yield from this reaction
but was unfortunately found to be racemic (Table 1). This
observation is entirely consistent with the model, alcohols
being less nucleophilic than amines and unable to trap the
initial contact radical ion pair before equilibration. An
additional complication in the alcohol series was the forma-
tion of byproducts (21) arising from cyclization of the
nucleophile onto phosphorus. This problem, which was ex-
acerbated by the inclusion of a quaternary center, discouraged
us from further work with the alcohols for the time being.13
Scheme 3. Enantioselective Formation of Heterocycles
nucleophilic attack occurs within the initial contact radical
ion pair and on the face of the alkene radical cation opposite
to that shielded by the departing phosphate group. The
cyclization of the next higher homologue 12 provided 14 in
very similar enantiomeric excess (Table 1) thereby demon-
strating the extension of the model to the formation of
piperidines.
A further substrate 15, prepared analogously to 11 and 12
from 3,3-dibenzyl-4-(N-Boc-benzylamino)butanal, resulted
in the formation of pyrrolidine 16 in 60% ee (Table 1). The
corrected ee values for 13, 14, and 16 (Table 1) are very
similar, which suggests comparable rates of cyclization in
the three cases. This is indicative of a very rapid attack on
the contact radical ion pair, which allows little room for
acceleration by the presence of a quaternary center or, indeed,
rate erosion due to the extra degree of freedom in 12.12
Hydrogenolysis of 9 cleanly removed the benzyl group,
which was replaced with a propargyl moiety. After cleavage
Acknowledgment. We thank the NSF (CHE 9986200)
for support of this work.
Supporting Information Available: Complete experi-
mental details and characterization data, including details of
assignment of configuration, for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035564X
(7) (a) Crich, D.; Ranganathan, K. J. Am. Chem. Soc. 2002, 124, 12422-
12423. (b) Crich, D.; Gastaldi, S. Tetrahedron Lett. 1998, 39, 9377-9380.
(8) Crich, D.; Ranganathan, K.; Rumthao, S.; Shirai, M. J. Org. Chem.
2003, 68, 2034-2037.
(12) Typical contact radical ion pairs escape to solvent-separated ion
pairs in dichlorobenzene with rate constants of ∼109 s-1 at room temperature
(Arnold, B. R.; Noukakis, D.; Farid, S.; Goodman, J. L.; Gould, I. R. J.
Am. Chem. Soc. 1995, 117, 4399-4400). Given that equilibration with the
solvent-separated ion pair is the stereorandomizing event, it can be estimated
that the nucleophilic cyclizations under investigation have rate constants
(9) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1987-
2012.
(10) Enantioselectivities of radical precurosors and of products were
assigned by GC and/or HPLC, as appropriate, over chiral stationary phases
that demonstrated baseline resolution of the corresponding racemic materials.
(11) Andre´s, J. M.; Herra´iz-Sierra, I.; Pedrosa, R.; Pe´rez-Encabo Eur. J.
Org. Chem. 2000, 1719-1726.
of g109 s-1
.
(13) There are indications,4e,7b however, of diastereoselective attack of
alcohols on alkene radical cations in similarly generated radical ionic contact
ion pairs when the counterion is the weaker nucleofuge, diethyl phosphate.
Org. Lett., Vol. 5, No. 20, 2003
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