Electron transfer initiated cyclizations: Cyclic acetal synthesis through carbon-carbon σ-bond activation [13]

Full text of DOI:10.1021/ja015526d

3842
J. Am. Chem. Soc. 2001, 123, 3842-3843
Table 1. ETIC Reactions with Various Substratesa
Electron Transfer Initiated Cyclizations: Cyclic
Acetal Synthesis through Carbon-Carbon σ-Bond
Activation
V. Satish Kumar and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh
Pittsburgh, PennsylVania 15260
ReceiVed January 9, 2001
Selective and transient activations of normally unreactive
functional groups are potentially quite useful processes in the
design of new synthetic transformations.1 The stability of carbon-
carbon σ-bonds and the wealth of methods available for their
construction suggest that devising methods for carbon-carbon
bond activation could create novel strategic opportunities in
organic synthesis. In this context we have initiated an investigation
of cyclization reactions involving the transient conversion of
homobenzylic ethers into potent electrophiles through single
electron oxidation.2 This communication details the development
of electron transfer initiated cyclization (ETIC) reactions, the use
of this method to synthesize several cyclic acetals, a mechanistic
study of the process, and a new approach to anomeric stereo-
control in furanose and pyranose synthesis.
Carbon-carbon bond cleaving reactions of homobenzylic ether
radical cations have been the focus of extensive mechanistic
studies.3 The benzylic carbon-carbon bonds of these highly
reactive species are significantly weakened, allowing for benzyl
radical displacement by a variety of poor nucleophiles. The
following criteria highlight the advantages of employing this
unique method of carbon-carbon bond activation in the design
of a new cyclization reaction (Scheme 1): (1) the generally inert
nature of the benzyl group facilitates substrate synthesis, (2) the
reaction conditions (hν, single electron acceptor) are essentially
neutral, allowing for the inclusion of acid- or base-sensitive
functionality in cyclization substrates, (3) the oxidation potential
of the substrate, and therefore the chemoselectivity of the
oxidation, can be altered in a rational manner by introducing
substituents onto the arene,4 (4) the reactivity of the system can
be tuned by introducing substituents at the benzylic position,5
and (5) the highly electrophilic nature of these radical cations
should allow a wide variety of nucleophiles to be employed in
the reaction.
a Reaction conditions: hν, N-methylquinolinium tetrafluoroborate
(1-2 equiv), NaOAc, DCE, tert-butylbenzene (4:1). b R ) n-octyl.
c Diastereomeric ratio. The major diastereomer is represented by the
structure in the Product column. Stereochemical assignments were based
on 1H NMR coupling constants except where noted. d Stereochemistry
was determined by NOE analysis. e Yield at 88% conversion. f The
relative stereochemistry of the starting material and the products was
not determined. g Yield at 91% conversion.
Scheme 1. Electron Transfer Initiated Cyclization
Attempts to initiate ETIC reactions utilizing homobenzylic ether
substrates with a variation of Arnold’s conditions3a (1,4-dicy-
anobenzene, CH3CN, Pyrex filtered irradiation, medium-pressure
mercury lamp) resulted in little or no product formation. We
hypothesized that rapid regeneration of starting material by return
electron transfer from the dicyanobenzene radical anion to the
substrate radical cation was the source of cyclization inefficiency.
To slow this unproductive process we initiated the cyclization
with cation-sensitized electron transfer,6 an effective method for
increasing the lifetimes of radical cations even in nonpolar
solvents.7 Irradiation of 1 (Scheme 1) in the presence of the
sensitizer N-methylquinolinium hexafluorophosphate (NMQPF6),
solid NaOAc (buffer), and tert-butylbenzene (cosensitizer) in 1,2-
dichloroethane dramatically increased the efficiency of the
reaction, proViding a 92% yield of 2 in only 20 min.
To explore the scope of this method a series of substrates were
prepared and subjected to sensitized electron-transfer conditions
(Table 1).8
(1) ActiVation of UnreactiVe Bonds and Organic Synthesis; Murai, S., Ed.;
Springer: Berlin, 1999.
(2) For a review of single electron oxidation in organic synthesis, see:
Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2550.
(3) (a) Arnold, D. R.; Lamont, L. J. Can. J. Chem. 1989, 67, 2119. (b)
Perrott, A. L.; Arnold, D. R. Can. J. Chem. 1992, 70, 272. (c) Arnold, D. R.;
Du, X.; Chen, J. Can. J. Chem. 1995, 73, 307. (d) Perrott, A. L.; de Lisjer, H.
J. P.; Arnold, D. R. Can. J. Chem. 1997, 75, 384. (e) Baciocchi, E.; Bietti,
M.; Putignani, L.; Steenken, S. J. Am. Chem. Soc. 1996, 118, 5952. (f)
Baciocchi, E.; Bietti, M.; Lanzalunga, O. Acc. Chem. Res. 2000, 33, 243. (g)
Chen, L.; Farahat, M. S.; Gan, H.; Farid, S.; Whitten, D. G. J. Am. Chem.
Soc. 1995, 117, 6398. (h) Freccero, M.; Pratt, A.; Albini, A.; Long, C. J. Am.
Chem. Soc. 1998, 120, 284.
This method has proven to be effective for accessing a range
of medium-sized rings (entries 2-3). The efficiency of the
cyclizations to form seven- and eight-membered rings is remark-
(6) Majima, T.; Pac, C.; Nakasone, A.; Sakurai, H. J. Am. Chem. Soc. 1981,
103, 4499.
(7) (a) Todd, W. P.; Dinnocenzo, J. P.; Farid, S.; Goodman, J. L.; Gould,
I. R. J. Am. Chem. Soc. 1991, 113, 3601. (b) Dockery, K. P.; Dinnocenzo, J.
P.; Farid, S.; Goodman, J. L.; Gould, I. R.; Todd, W. P. J. Am. Chem. Soc.
1997, 119, 1876.
(4) Howell, J. O.; Goncalves, J. M.; Amatore, C.; Klasinc, L.; Wightman,
R. M.; Kochi, J. K. J. Am. Chem. Soc. 1984, 106, 3968.
(5) Popielarz, R.; Arnold, D. R. J. Am. Chem. Soc. 1990, 112, 3068.
1
(8) All new compounds have been characterized by H NMR, 13C NMR,
IR, and HRMS. See the Supporting Information for details.
10.1021/ja015526d CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/18/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 16, 2001 3843
Scheme 2. Stereoselective Cyclizations through Bicyclic
Intermediates
Figure 1. Proposed mechanistic pathways.
able given the absence of conformational constraints in the
substrates.9 Attempts to prepare small, strained rings were not
successful. In a direct competition, the formation of furanose
structures is preferred relative to the formation of pyranose
structures (entries 4 and 5). Protection of the secondary hydroxyl
as a bulky tert-butyl ether reverses this selectivity (entries 6 and
7). Alkoxyalkyl ethers can also serve as the nucleophilic group
in the reaction (entry 8). In this example, oxonium ion dealkylation
follows cyclization. The compatability of the sensitive epoxy
alcohol (entry 9) with the reaction conditions demonstrates that
strong acid is not produced in this procedure.
An analysis of the results in Table 1 led us to propose the
mechanistic scheme for the process shown in Figure 1. A
reversible and essentially isoenergetic electron transfer from the
substrate to the radical cation of tert-butylbenzene (generated from
electron transfer to the photoexcited N-methylquinolinium ion)
yields the substrate radical cation. The substrate radical cation
can cyclize through two pathways: an associative SN2-type
pathway leading to stereochemical inversion at the electrophilic
center or a dissociative, stereorandom SN1-type pathway.
The stereospecificity observed in entry 4 indicates that this
substrate cyclizes predominantly through the associative path-
way.10 The lack of stereospecificity observed in entries 5-8,
however, shows that cyclizations of several substrates proceed
at least in part through the dissociative pathway. The extent to
which cyclizations partition between the associative and dissocia-
tive pathways follows expected trends based on substrate structure.
Lowering the rate of the associative pathway by employing a weak
or bulky nucleophile or generating steric repulsion in the transition
state leads to a greater contribution from the dissociative pathway.
When cyclization through the dissociative pathway proceeds
slowly the intermediate carbocation can recombine with the benzyl
radical to reform the radical cation. Reduction of the radical cation
by tert-butylbenzene regenerates starting material. The starting
material recovered from the cyclization of the particularly slowly
reacting ether in entry 9 was a 1:1 mixture of diastereomers,
providing evidence for this pathway.
proposal, the cyclization of acetonide 3 is consistent with the
initial formation of bicycle 4, with the alkoxy group oriented on
the sterically less-encumbered convex face of the bicyclo[3.3.0]
ring system. Hydrolytic decomposition of 4 provides dideoxyri-
boside 5 in 74% yield as an 11:1 mixture of diastereomers,
representing a 110-fold reversal in the stereochemical outcome
of the reaction relative to the cyclization of the parent diol. The
involvement of the dissociative pathway in this reaction was
confirmed through the observation that the cyclization of dia-
stereomeric acetonide 6 provided a product mixture identical with
that from 3.
The generation of bicyclic oxonium ions has also been
employed for the synthesis of pyranosides (Scheme 2). In this
case the outcome of the ETIC reaction of epoxide 7 is consistent
with an initial formation of epioxonium ion 8 followed by
nucleophilic attack by adventitious water at the more substituted
center, forming pyranoside 9 as a >19:1 mixture of diastereomers
in 49% yield. In addition to the excellent diastereoselectivity
observed in this reaction, the intermediacy of the epioxonium ion
suggests that this methodology could be useful for the initiation
of polyether cascade cyclizations11 under neutral conditions. The
expected predominance of the dissociative pathway in this reaction
was confirmed by the formation of 9 in a 9:1 diastereomeric ratio
from epimeric epoxide 10.
In summary, we have developed a new cyclization reaction
that proceeds through an experimentally simple electron-transfer
mediated carbon-carbon σ-bond activation pathway. Cyclizations
proceed through either an associative or a dissociative mechanism,
with the latter providing access to stabilized carbocations under
neutral conditions. This approach has been utilized to form
bicyclic oxonium ions as intermediates in the diastereoselective
construction of furanoside and pyranoside systems, thus leading
to a unique strategy for controlling anomeric stereochemistry.
Recognizing that forcing ETIC reactions to proceed through
the dissociative pathway results in transient, chemoselectiVe
carbocation formation under neutral conditions led us to envision
opportunities for the design of unique regio- and stereocontrolled
reactions. We proposed that single electron oxidation of a
homobenzylic ether tethered to a very weakly nucleophilic cyclic
ether could provide a bicyclic intermediate in which stereo-
selecontrol of the nascent anomeric center would be dictated by
the energetic preference of bulky substituents for the less sterically
hindered face of the ring system (Scheme 2). In support of this
Acknowledgment. This work was supported by the University of
Pittsburgh. We thank Dr. Fu-Tian Lin for assistance with stereochemical
analyses and Professors Scott Nelson, Ted Cohen, and Craig Wilcox for
helpful discussions.
Supporting Information Available: Synthetic schemes and proce-
dures for cyclization substrates, and procedures and characterizations for
cyclization reactions (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA015526D
(9) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(10) These product ratios could also result from an initial dissociation
followed by a rapid cyclization relative to benzyl radical diffusion.
(11) For a review see: Koert, U. Synthesis 1995, 115.