Diastereoselectivity in the cyclization of alkene radical cations generated under non-oxidizing conditions: Contact ion pairs and memory effects

Article abstract of DOI:10.1021/ja027893a

A series of highly diastereomerically enriched 1,5-dimethyl-, 2,5-dimethyl-, and 3,5-dimethyl-N-benzyl-5-nitro-4-(diphenylphosphatoxy)hexylamines were exposed to tributyltin hydride and AIBN in benzene at reflux. The ensuing reactions, interpreted in term

Full text of DOI:10.1021/ja027893a

Published on Web 09/26/2002
Diastereoselectivity in the Cyclization of Alkene Radical Cations Generated
under Non-Oxidizing Conditions: Contact Ion Pairs and Memory Effects
David Crich* and Krishnakumar Ranganathan
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
Received July 28, 2002
Scheme 1. Preparation of anti- and syn-8
Appropriately substituted â-(phosphatoxy)alkyl radicals suffer
radical ionic fragmentation to highly organized contact ion pairs
comprised of alkene radical cations and phosphate anions.1-3 In
the absence of nucleophiles, in nonpolar solvents, recombination
occurs on a time scale competitive with reorganization within the
contact ion pair, as repeatedly demonstrated by stereochemical and
isotopic labeling studies, to give either the initial4 or the rearranged
radical.5,6 When a suitable nucleophile is included, the ion pair may
be trapped, leading to the formation of heterocycles7,8 and, through
radical/polar crossover processes, to alkaloid-like skeleta.9,10 Al-
though the alkene radical cations undergoing nucleophilic attack
in these processes are formally planar and achiral, their association
with the anion in a contact ion pair raises the possibility of enantio-
and diastereoselective reactions that exhibit memory11 of the
stereogenicity of the precursor radical provided that trapping takes
place before equilibration of the various possible ion pairs. The
potential for such stereoselective reactions marks a significant
difference between the present fragmentation approach to alkene
radical cations, aside from the non-oxidizing conditions, and the
more classical entries12,13 involving one-electron oxidation of
alkenes. Here, we reduce the concept to practice and illustrate the
Scheme 2. Cyclization of anti- and syn-8
dependence of the diastereoselectivity on substitution.
We first investigated the effect of a stereogenic center adjacent
to the alkene radical cation. A suitable substrate was assembled
from the known alcohol 1 as set out in Scheme 1. In this sequence,
reduction of the ketone 5 produced a 1/1 anti/syn mixture of the
nitro-aldol 6 which was conveniently separated at the level of the
phosphates 7, whose stereochemistry was assigned on the basis of
coupling constant and NOE data. The individual isomers were then
deprotected by exposure to TMSOTf and lutidine to give the amines
8. These were then cyclized individually with tributyltin hydride
and AIBN in benzene at reflux, giving in both cases a predominance
of trans-N-benzyl-3-methyl-2-isopropylpyrrolidine 9 over the cis-
isomer 10 (Scheme 2).14
Two further pairs of diastereomeric substrates, with backbone
substituents â- and γ- to the site of reaction, were prepared by
unambiguous, stereocontrolled routes15 and subjected to the cy-
clization conditions. The tin hydride-mediated cyclizations of both
anti- and syn-11 were highly diastereoselective and gave the
pyrrolidines 12 and 13, respectively, that is, both with effective
inversion of configuration at carbon (Scheme 3).
The cyclizations of anti- and syn-14, conducted in the standard
manner with tributyltin hydride and AIBN in benzene at reflux,
were both diastereoselective for the product arising from apparent
backside attack on the parent phosphates (Scheme 4). Additionally,
in this series, significant amounts of the tricyclic product 17, whose
stereochemistry was unambiguously assigned by NOE measure-
ments, were isolated. The formation of considerable amounts of
17 in these latter cyclizations presumably arises from the high
degree of steric compression following nucleophilic ring closure
according to the transition state for the formation of 15, which
results in a further oxidative radical cyclization onto the benzyl
group. Product 17 is therefore a derivative of the cis-pyrrolidine
15 and has been incorporated as such in the de for the overall
cyclization.
Of the six cyclizations presented, all but one conform to a simple
model for formation of the major diastereomer. Thus, the initial
radical, generated on reaction with tin hydride, undergoes frag-
mentation to a contact alkene radical cation/phosphate anion pair,
wherein the anion shields the face of the radical cation from which
it has just departed. Nucleophilic attack then takes place on the
* To whom correspondence should be addressed. E-mail: dcrich@uic.edu.
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10.1021/ja027893a CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Cyclization of anti- and syn-11
The invocation of chairlike transition states in cyclizations, with
the maximum number of substituents pseudoequatorial, resulting
in the formation of five-membered rings, has been immensely
popular since put forward by Beckwith16 for 5-hexenyl radical
cyclizations and legitimized computationally.17,18 The present model
for alkene radical cation cyclizations differs fundamentally from
the Beckwith/Houk one for radical cyclizations as, with the
exception of pervading steric interactions in the initial contact ion
pair, it takes into account the configuration of the precursor to the
reactive intermediate.
Although the chemistry described herein has been conducted with
â-(phosphatoxy)alkyl radicals, we fully anticipate, given the close
parallels in their known rearrangements,19,20 that the corresponding
â-(sulfatoxy)alkyl,21 â-(nitroxy)alkyl,21,22 â-(acyloxy)alkyl,23 and
â-halogenoalkyl radicals24 will function analogously albeit on
different time scales.
Scheme 4. Cyclization of anti- and syn-14
Acknowledgment. We thank the NSF (CHE 9986200) for
support of this work.
Supporting Information Available: Complete experimental details
and characterization data, including details of assignment of configu-
ration, for all new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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(15) To be described in full in a subsequent paper.
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opposite face of the contact ion pair, resulting in cyclization with
effective inversion of configuration at the site of the original C-O
bond. These cyclizations may be rationalized by chairlike transition
states with nucleophilic attack on the initial contact ion pair
(Schemes 2-4). In three of these, all substituents are pseudoequa-
torial, and the chairlike model seems appropriate. In two examples,
however (anti-11 f 12 and anti-14 f 15), the methyl substituent
is pseudoaxial, and it is possible that alternative twist boatlike
transition states are favored in these cases. Indeed, the higher de
for the cyclization of anti-14 over that of syn-14 strongly suggests
that the chairlike transition state model cannot be the predominant
one in this pair of diastereomers. Boatlike transition states are
presumably not effective because of bowspit interactions with the
pseudoaxial methyl group in the trisubstituted alkene radical cation.
Cyclization of the initial contact ion pair arising from anti-8 through
a chairlike transition state would be strongly disfavored because
of 1,3A strain this would engender in the alkene radical cation
(Scheme 2). This particular radical cation/anion pair therefore
undergoes equilibration of the phosphate between the two faces of
the system and eventually cyclizes via a transition state akin to
that for syn-8 f 9.
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