Exploiting phosphonate chemistry in metal-mediated dearomatization: Stereoselective construction of functionalized spirolactams from arene ruthenium complexes

Article abstract of DOI:10.1021/ja058342y

Arene ruthenium complexes possessing β-amido phosphonate side chains participate in intramolecular spirocyclization reactions to deliver stable cyclohexadienyl ruthenium adducts. Spirocyclization is accomplished via a tandem two-step sequence that involve

Full text of DOI:10.1021/ja058342y

Published on Web 02/22/2006
Exploiting Phosphonate Chemistry in Metal-Mediated Dearomatization:
Stereoselective Construction of Functionalized Spirolactams from Arene
Ruthenium Complexes
F. Christopher Pigge,*,† John J. Coniglio,‡ and Rashmi Dalvi†
Department of Chemistry, UniVersity of Iowa, 305 Chemistry Building, Iowa City, Iowa 52242, and Department of
Chemistry & Biochemistry, UniVersity of Missouri - St. Louis, One UniVersity BouleVard, St. Louis, Missouri, 63121
Received December 8, 2005; E-mail: chris-pigge@uiowa.edu
η6-Arene metal complexes are well recognized as versatile
Table 1. Construction of Olefinated Spirocyclic Lactam Ruthenium
Complexes
synthetic intermediates due to the facility with which the arene
ligand can be functionalized.1 In recent years, developing stereo-
contolled methods suitable for efficiently converting such complexes
into nonaromatic (alicyclic) products has attracted renewed interest.2
Recent examples of diastereoselective metal-mediated dearomati-
zation involving tricarbonyl Cr(0) and Mo(0) arene complexes have
been reported.3,4 More reactive cationic arene Mn(CO)3 complexes
have also been elaborated to substituted cyclohexadienes.5
Arene ruthenium complexes, particularly those incorporating a
CpRu(II) fragment, are easily prepared in high yield using condi-
tions compatible with functionalized arene ligands.6 Their use as
synthetic building blocks, however, has not been extensively
explored, and aside from our own work, reaction manifolds leading
to nonaromatic products are virtually unknown.7 In this context,
we have found that readily available benzyl amide ruthenium
complexes can be converted to diastereomerically pure metal-free
spirolactam derivatives. This net Ru-mediated dearomatization is
accomplished via intramolecular nucleophilic aromatic addition of
a phosphonate anion to an electrophilic (arene)Ru moiety followed
by HWE olefination. The resulting cyclohexadienyl ruthenium
products are then subjected to stereocontrolled nucleophilic de-
metalation performed under oxidative conditions.
Previously, we have reported the preparation of spirolactams
exhibiting the 2-azaspiro[4.5]decane framework (e.g., 1) from
methoxy-substituted (η6-N-benzyl acetoacetamide)RuCp+ com-
plexes (2).8 The conversion 2 f 1 entails tandem nucleophilic
aromatic addition/enolate O-alkylation, followed by oxidative
demetalation. While effective, the procedure suffers from several
products of such a reaction (i.e., cyclohexadienyl complexes) would
retain a phosphonate group, thereby potentially allowing further
elaboration via inter alia olefination reactions; the enamide products
obtained after olefination would be devoid of acid-sensitive enol
ether groups. This last feature was viewed as particularly desirable
as it was hoped that the added stability of such complexes would
facilitate development of truly general demetalation procedures.
The preparation of arene ruthenium substrates possessing â-
amido phosphonate side chains (3, 4) was accomplished in high
yield using standard organic/organometallic procedures (see Sup-
porting Information). Gratifyingly, treatment of 3 or 4 in THF (or
DMF) with excess NaH at room temperature for ∼30 min fol-
lowed by addition of aldehyde afforded the desired azaspirocyclic
ruthenium complexes (Table 1). Several aliphatic and aromatic
aldehydes were employed in this reaction, and all were found to
provide Z-configured olefinated lactams stereoselectively. Acetone
and cyclohexanone, however, were not effective participants, and
other ketones were not investigated. Deprotonation of the activated
methylene group in the arene ruthenium side chain presumably leads
to rapid spirocyclization with nucleophilic aromatic addition
occurring exclusively from the face opposite the RuCp fragment.
It is noteworthy that incorporation of an electron-donating methoxy
group para to the amido phosphonate side chain (i.e., 4) has no
noticeable effect upon the efficiency of this process. A second in
situ deprotonation then generates a reactive phosphonate anion that
shortcomings, notably the modest isolated yields sometimes
encountered in the enolate alkylation step, the necessary inclusion
of an acid-sensitive enol ether in the lactam periphery, and the
requirement of a strategically positioned methoxy substituent in
order to achieve controlled demetalation. We have largely amelio-
rated these drawbacks through the use of N-benzyl-â-amido
phosphonates as spirolactam precursors.
The decision to examine â-amido phosphonates as spirocycliza-
tion substrates was predicated upon the following considerations:
generation of a nucleophilic phosphonate anion capable of partici-
pating in aromatic addition reactions should be straightforward; the
† University of Iowa.
‡ University of Missouri - St. Louis.
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J. AM. CHEM. SOC. 2006, 128, 3498-3499
10.1021/ja058342y CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
participates in Horner-Wadsworth-Emmons olefination after
addition of the aldehyde component. Cyclohexadienyl complexes
5-14 (Table 1) were obtained as air-stable materials in yields
ranging from good to excellent after isolation via conventional
purification techniques (recrystallization and/or silica gel chroma-
tography).
Methoxy-functionalized cyclohexadienyl ruthenium products
display reactivity similar to their enol ether-derived counterparts
(vide supra)8b in that direct oxidative demetalation could be
accomplished simply by treatment with a mild oxidant such as
CuCl2. Thus, exposure of 10 to the conditions indicated in eq 1
afforded the corresponding metal-free azaspirocyclic dienone 15
in good yield. Significantly, unsubstituted cyclohexadienyl com-
plexes also proved to be viable substrates for demetalation under
slightly modified reaction conditions. As illustrated in eq 2,
provides access to potentially synthetically versatile heterocyclic
building blocks but also presents an opportunity for development
of asymmetric versions of this spirocyclization method. Our initial
approach toward achieving this latter objective entails utilization
of a chiral nonracemic R-substituted benzylamine as a ruthenium
ligand precursor and is illustrated in Scheme 2. Conversion of
(S)-(-)-R-methyl benzylamine (>98% ee) to arene ruthenium com-
plex 20 was easily accomplished. Tandem intramolecular nucleo-
philic aromatic addition/intermolecular HWE olefination afforded
cyclohexadienyl complex 21 in high yield. It was anticipated that
the presence of the R-methyl substituent would influence the regio-
selectivity of nucleophilic addition to the diastereotopic cyclohexa-
dienyl ligand. This, indeed, proved to be the case as exposure of
21 to conditions of nucleophilic oxidative demetalation gave dienol
(-)-22 as a single diastero- and enantiomerically pure stereoisomer.
In conclusion, an experimentally mild and stereoselective
ruthenium-mediated dearomatization procedure has been developed
in which simple and readily available (arene)Ru(II) complexes are
converted to unique and heavily functionalized 2-azaspiro[4.5]-
decane derivatives. This approach has coupled activating and
stereodirecting effects of a CpRu(II) fragment with organophos-
phonate chemistry in order to access this pharmacologically
intriguing heterocyclic ring system.11 We are currently exploring
the utilization of azaspirodecanes as synthetic building blocks while
also investigating other Ru-promoted dearomatization reaction
manifolds
treatment of 5 with CuBr2 in MeOH under a CO atmosphere
resulted in clean conversion to methoxy-substituted diene 16.
Moreover, 16 was obtained as a single diastereomer exhibiting the
relative stereochemistry shown. In addition, the CpRu(II) fragment
was also recovered from the reaction in the form of bromodicar-
bonyl adduct 17.9
Acknowledgment. We thank the National Science Foundation
for generous financial support (CHE-0544572).
Methoxy diene 16 is envisioned to evolve from nucleophilic
addition of methanol to one terminus of a cyclohexadienyl cation-
like species generated via oxidation of 5. The stereochemical
outcome reflects nucleophilic addition to the dienyl ligand from
the face opposite the Ru fragment.10 Performing the transformation
under a blanket of CO (as compared to Ar) resulted in higher
isolated yields of 16 (presumably through decomplexation of an
η4 intermediate) and provided a convenient means of recovering
the transition metal center. Cupric bromide proved to be a more
efficient oxidant than CuCl2 in this transformation, an effect that
we ascribe to the better solubility of CuBr2 in organic solvents.
The scope of the nucleophilic oxidative demetalation depicted
in eq 2 has been briefly investigated. Performing the reaction in a
mixture of THF/H2O leads to dienol products as shown in Scheme
1. In each case a single diastereomer exhibiting the relative
stereochemistry indicated is obtained. Facile addition of H2O to
the cyclohexadienyl ligand in substrates such as 5 and 9 not only
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Scheme 1
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