Carbolithiation for the Generation of Cyclooctadienyl Anions and Tandem Electrocyclization/Alkylation to Functionalized cis-Bicyclo[3.3.0]octenes

Article abstract of DOI:10.1021/ja049353e

A powerful cascade reaction process for the construction of functionalized cis-bicyclo[3.3.0]octenes has been developed. Carbolithiation of 3-methylene-1,4-cyclooctadiene with 1°, 2°, or 3° alkyllithium reagents leads to cyclooctadienyl anions, which unde

Full text of DOI:10.1021/ja049353e

Published on Web 03/02/2004
Carbolithiation for the Generation of Cyclooctadienyl Anions and Tandem
Electrocyclization/Alkylation to Functionalized cis-Bicyclo[3.3.0]octenes
David R. Williams* and Jonathan T. Reeves
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405-7102
Received February 5, 2004; E-mail: williamd@indiana.edu
Thermally induced “valence tautomerism” of 1,3,5-cycloocta-
triene to cis-bicyclo[4.2.0]octa-2,4-diene was first reported by A.
C. Cope1 in 1950 and was later studied in detail by Winstein.2 The
stereospecific nature of the electrocyclization, and indeed all
pericyclic reactions, was subsequently rationalized in terms of
conservation of orbital symmetry by Woodward and Hoffmann.3
Their conclusions regarding electrocyclic reactions predicted that
a charged species should behave in the same way as the corre-
sponding isoelectronic neutral system.3a This prediction was
confirmed for the anionic equivalent of the cyclooctatriene system
with the first example of electrocyclization of a pentadienyl anion
as shown by the disrotatory conversion of cyclooctadienyllithium
to cis-bicyclo[3.3.0]octenyllithium reported by Bates in 1969.4
Subsequently, electrocyclization of 1,5-diphenylpentadienyl anion
to isomeric diphenylcyclopentenes was disclosed.5 Additional
reports have described unsuccessful attempts for cyclization of
cyclic6 and acyclic7 pentadienyl anions. To utilize the facile nature
of the cyclooctadienyl electrocyclization, we proposed generation
of the requisite pentadienyl anion through carbolithiation8 of triene
1 (Scheme 1). Disrotatory ring closure of the resultant pentadienyl
anion 2 to bicyclic allyl anion 3 and subsequent electrophilic capture
would provide the functionalized cis-bicyclo[3.3.0]octene 4. This
reaction cascade would allow formation of three C-C bonds and
three stereocenters in a single operation from simple starting
materials. We report herein the successful realization of this pro-
cess, its scope, and its application to the preparation of a linear
triquinane.
alkylated or protonated 2 in the product mixture implies electro-
cyclization is highly favored.12
The reaction scope with respect to alkyllithium and electrophile
was examined (Table 1). Reactions with secondary and tertiary
alkyllithiums (entries 1-5, 8-10) proceeded in Et2O, while primary
alkyllithium reagents (entries 6-7) required hexanes and 1 equiv
of a diamine additive such as TMEDA or preferably (-)-sparteine
to effect carbolithiation.13 Modest asymmetric induction was
observed using n-BuLi‚(-)-sparteine (entry 6).14 Alkyllithium
reagents generated in situ from the corresponding iodides by lithium/
halogen exchange with t-BuLi reacted smoothly (entries 5 and 7),
demonstrating the potential for incorporation of base-stable func-
tionality. Quenching with heteroatom electrophiles provided access
to useful allylic sulfide, alcohol, and silane moieties (entries 1-3).
Alkylation with ketones, aldehydes, and CO2 efficiently led to
formation of a new C-C bond (entries 4-7). Transmetalation of
the intermediate allyllithium species to copper was possible using
CuCN/LiCl.15 This permitted conjugate additions to unsaturated
ketones and esters (entry 8 and Scheme 2, vide infra) in the presence
of TMSCl, and alkylations with alkyl iodide (entry 9) and epoxide
(entry 10) electrophiles also proved feasible.
Scheme 1. Cascade Carbolithiation/Electrocyclization/Alkylation
Scheme 2 a
Wittig methylenation9 of readily available 2,7-cyclooctadienone10
provided 3-methylene-1,4-cyclooctadiene (1). Preliminary studies
employing tert-butyllithium for carbolithiation revealed Et2O as the
optimal solvent (eq 1). Thus, dropwise addition of 1.1 equiv of
t-BuLi to an Et2O solution of 1 at -78 °C, stirring at room
temperature for 1.5 h, and quenching with benzophenone at -78
°C provided a 65% yield of bicycle 5 as a single diastereomer.11
Generation of the pentadienyl carbanion 2 permits the concerted,
disrotatory ring closure to the cis-fused allyl anion 3. Introduction
of the electrophile proceeds via stereocontrolled alkylation of the
more accessible convex face of the cis-bicyclo[3.3.0]octenyl anion.
While factors such as the additional conjugation in 2, the introduc-
tion of ring strain in 3, and the formation of a new C-C bond
might suggest an equilibrium state of 2 and 3, the absence of
a Conditions: (a) n-BuLi, (-)-sparteine, hexanes, -78 °C to room
temperature, 1 h; CuCN‚2 LiCl, THF, -78 °C; ethyl acrylate, TMSCl, -78
°C to room temperature. (b) i. LiOH, THF/H2O; ii. N-(phenylselenyl)phthal-
imide, n-Bu3P, THF. (c) n-Bu3SnH, AIBN, PhH, reflux.
The rapid preparation of a linear triquinane using the carbo-
lithiation/electrocyclization/conjugate addition cascade is detailed
in Scheme 2. Carbolithiation/electrocyclization of 1 using n-BuLi‚
(-)-sparteine followed by transmetalation to copper and 1,4-addition
to ethyl acrylate provided the adduct 16 in 70% yield (dr ) 8.4:1).
Conversion to phenylselenyl ester16 17 and acyl radical cyclization17
provided triquinane 18 in 81% yield as a single diastereomer.18
9
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J. AM. CHEM. SOC. 2004, 126, 3434-3435
10.1021/ja049353e CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Scope of Cascade Carbolithiation/Electrocyclization/Alkylation Reactiona
a
b
c
Reaction conducted with 1 in Et2O (entries 1-5, 8-10) or hexanes/1 equiv (-)-sparteine (entries 6-7). Isolated yields after purification. Diastereomeric
ratios determined by 1H NMR of crude product mixtures. Generated from the corresponding iodides by treatment with t-BuLi (2.2 equiv) and cannulation
away from precipitated LiI. Enantiomeric excesses of 9 and 16% determined by Mosher’s ester analysis of each diastereomer. A solution of CuCN (1
equiv) and LiCl (2 equiv) in THF added prior to electrophile.
d
e
f
In conclusion, a powerful cascade reaction process for the rapid
construction of functionalized cis-bicyclo[3.3.0]octenes has been
References
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employed. Transmetalation from lithium to copper prior to elec-
trophilic quench allows access to the cuprate manifold of reactivity.
The expedient preparation of a linear triquinane using this
methodology should prove useful for natural products synthesis.
This process represents the first synthetic application of the
electrocyclization of a pentadienyl anion, and the generation of a
reaction-competent carbanion by a C-C bond-forming carbolithia-
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Acknowledgment. We gratefully acknowledge the National
Institutes of Health for financial support (GM-41560) and a National
Research Service Award to J.T.R. (GM-068318).
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Supporting Information Available: Full experimental details, 1H
NMR spectra of all compounds, and COSY and NOESY spectra of
representative compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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