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Chem. Rev. 1996, 96, 339−363
Manganese(III)-Based Oxidative Free-Radical Cyclizations
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02254-9110 Received June 26, 1995 (Revised Manuscript Received September 27, 1995 ) A. Oxidative Free-Radical Cyclizations A. Mechanistic Considerations 2. Ce(IV), Fe(III), V(V), etc.
D. Further Oxidation of the Product A. Oxidation by Mn(III) B. Oxidation by Cu(OAc)2 Barry B. Snider is a graduate of the University of Michigan (B.S.) and Harvard University (Ph.D.). After postdoctoral training at Columbia D. Addition to Nitriles and Carbon Monoxide University, he joined the faculty of Princeton University. Since 1981 hehas been at Brandeis University, where he is now Professor of Chemistry.
E. Hydrogen Abstraction He has been an Alfred P. Sloan fellow, a Dreyfus Teacher Scholar and IV. Monocyclization an ACS Cope Scholar. His research interests are in the area of synthetic A. Radicals Derived from Acids methods development and natural product synthesis. Current interestsinclude oxidative free-radical cyclizations, Lewis acid-induced and -cata- B. Radicals Derived from â-Keto Esters and lyzed reactions, ene reactions, and the synthesis of guanidine-containing â-Diketones That Lead to Cycloalkanones natural products.
-Unsubstituted â-Keto Esters -Substituted â-Keto Esters during the past 30 years.1- A typical, widely used procedure involves the reduction of a halide or otherfunctional group to a radical with R C. Radicals Derived from â-Keto Esters, â-Diketones, and Malonate Esters That Lead by cyclization and reduction of the resulting radical to a hydrocarbon in the chain propagation steps (eq D. Radicals Derived from â-Keto Esters, â-Keto 1). While this sequence often gives high yields of Amides, and Malonate Esters That Lead toLactones and Lactams E. Additions to Aromatic Rings V. Tandem Cyclizations A. Additions to a Double Bond and then an B. Additions to Two Double Bonds VI. Triple and Higher Cyclizations products, this approach is limited, leading torelatively unfunctionalized products resulting from VII. Asymmetric Induction a net two-electron reduction. Oxidative free-radical VIII. Annulations cyclization in which the initial radical is generated IX. Oxidation of Ketones oxidatively and/or the cyclic radical is terminated X. Oxidation of Enol Ethers and Enamines oxidatively, has considerable synthetic potential, since more highly functionalized products can be XII. Synthetic Applications prepared from simple precursors (eq 2).
XIII. Acknowledgments XIV. References and Notes A. Oxidative Free-Radical Cyclizations
Radical cyclization of alkenes has become a valu- Oxidative formation of an acyclic radical involves able method for the synthesis of cyclic compounds the formal loss of a hydrogen atom. In practical 1996 American Chemical Society 340 Chemical Reviews, 1996, Vol. 96, No. 1
terms this is often accomplished by loss of a proton ing the one-electron oxidant Mn(OAc)3 in acetic acid and oxidation of the resulting anion with a one- at reflux (115 °C) generates the carboxymethyl electron oxidant to generate a radical. The advan- radical. This adds to alkenes to give a radical, which tage of this method of radical formation is that the is oxidized by a second equivalent of Mn(OAc)3 to give precursor is simple and usually readily available. A a γ-lactone (eq 3). This sequence of steps generates potential disadvantage is that the cyclization productmay also be susceptible to further deprotonation andoxidation.
Oxidative termination of radical cyclizations is advantageous since more highly functionalized,versatile reductive terminations that deliver a hydrogen atom.
Oxidation of the radical to a cation by one-electron a radical oxidatively from acetic acid, efficiently forms oxidants, oxidation of the radical to an alkene with a carbon carbon bond, and produces a synthetically Cu(II) carboxylates, and reaction with heteroatom useful γ-lactone by oxidation of the carbon-centered donors to give halides or sulfides are all oxidative These oxidative additions have been terminations. The atom-transfer reactions developed extensively explored over the past 25 years and by Curran that afford halides, and the thio transfer have been reviewed recently.8 11 reactions developed by Barton are broadly useful Mn(III)-based oxidative cyclization of unsaturated procedures for oxidative termination of radical acids is not possible, since the optimal solvent for this reaction, acetic acid, will be oxidized preferentially.
Some early synthetically useful radical cyclizations Heiba and Dessau reported in 1974 that â-keto were carried out under oxidative conditions. Julia esters and related dicarbonyl compounds are oxidized extensively explored the radical cyclization of to radicals at 25 70 °C in acetic acid. For instance, unsaturated cyanoacetates.4 Oxidation of 1 with
oxidation of ethyl acetoacetate in the presence of benzoyl peroxide in cyclohexane at reflux generates styrene affords a dihydrofuran (eq 4).12 The applica- radical 2 by hydrogen abstraction. Radical 2 cyclizes
to give cyclopentylmethyl radical 3. Since the only
termination possibility is the slow abstraction of a
hydrogen from cyclohexane, and the cyclization of 2
is reversible, the more stable cyclohexyl radical 4 is
formed and abstracts a hydrogen from cyclohexane
to give 5. These reactions proceed by oxidative
initiation, but are terminated reductively. Breslow
tion of Mn(III) to oxidative free-radical cyclizations reported the oxidative cyclization of farnesyl acetate was investigated initially by Corey, Fristad, and (6) with benzoyl peroxide, cuprous chloride, and
Corey and Kang reported the oxidative cupric benzoate in acetonitrile at reflux to generate cyclization of unsaturated â-keto acids in 1984.13 In 20 30% of 7.5 Both the initiation and termination
1985, we described the oxidative cyclization of un- of this tandem radical cyclization are oxidative.
saturated â-keto esters,14 and Fristad surveyed the Unfortunately, initiation of a radical cyclization by cyclization of unsaturated malonic and cyanoacetic addition of the benzoyloxy radical to an alkene does acids.15 In the past decade, Mn(III)-based oxidative not appear to be generally applicable.
free-radical cyclizations and annulations have beenextensively investigated in my laboratory14,16 46 by Bertrand,47 52 Chuang,53- Citterio,58- Cossy,71- This review is restricted to oxidative free-radical cyclizations and annulations; intermolecular addi-tions have been reviewed recently and are notcovered.8 11 While the vast majority of the work has used Mn(III) or Mn(III)/Cu(II), other one-electronoxidants, most notably Ce(IV), Fe(III), and Cu(II),have also been employed.
The Mn(III)-based oxidative free-radical cyclization of 8a and 8b serves to introduce the factors that need
to be understood to use these reactions in synthesis.
Oxidative cyclization of â-keto ester 8a with Mn(OAc)3
affords a complex mixture of products. Primary and
secondary radicals, such as 12, are not oxidized by
Mn(III). Heiba and Dessau found that Cu(OAc)2
oxidizes secondary radicals 350 times faster than
B. Mn(OAc)
Mn(OAc)3 does and that the two reagents can be used together.113 Oxidative cyclization of 8a with 2 equiv
The oxidative addition of acetic acid to alkenes of Mn(OAc)3 and 0.1 1 equiv of Cu(OAc) reported by Heiba and Dessau6 and Bush and acid affords 71% of 13a. Cu(OAc)2 reacts with radical
Finkbeiner7 in 1968 provides the basis for a general 12a to give a Cu(III) intermediate that undergoes
approach to oxidative free-radical cyclization. Heat- oxidative elimination to give 13a.14,24
Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 341
oxidative cyclization of 8b affords 56% of 13b as the
We found that a similar mechanism is operative major product.
in the oxidation of -alkyl â-keto esters (see eq 5).19 Enolization to give 18 is slow; electron transfer with
loss of Mn(II) to give 19 is rapid. The rate of reaction
is therefore independent of alkene concentration or
the nature of the tether in cyclizations. Radical 19
reacts from the geometry shown as determined by
analysis of the stereochemistry of the products as
discussed below. Comparable regio- and stereochem-
ical results are obtained from a series of Mn(III)-
based oxidative cyclizations and iodine or bromine
The first step in the reaction is the loss of a proton atom-transfer cyclization.29 This indicates that free to give the Mn(III) enolate 9. The next step of the
radical 19 is involved in the Mn(III)-mediated oxida-
reaction could involve cyclization of the unsaturated tive cyclizations. Some differences in regiochemistry Mn(III) enolate 9 to give cyclic radical 12. This is
or stereochemistry between oxidative cyclizations and the operative pathway for R H. Alternatively, loss atom-transfer cyclizations would be expected if a of Mn(II) could give the Mn-free free radical 10. This
Mn(III)-complexed radical were involved. Baciocchi is the operative pathway for R and Giese showed by competitive rate measurements nistic considerations are discussed below in the that free radicals are generated in the oxidation of section on initiation. Cyclization of 10b from the
conformation shown gives radical 12b stereo- and
nitrate.119 ESR studies have demonstrated that free regiospecifically as discussed in the section on cy- clization. Finally, Cu(II) oxidation of 12 gives 13
regio- and stereospecifically as discussed below in the On the other hand, we found that the enolization section on termination.
of -unsubstituted â-keto esters is fast and reversible, and electron transfer to give the radical is very slow(see eq 6).19 The rate-determining step depends on A. Mechanistic Considerations
The mechanism of oxidation of monocarbonyl sub- strates with Mn(OAc)3 2H 2O has been extensively studied. Fristad and Peterson showed that the rate-determining step in the oxidation of acetic acid byMn(OAc)3 2H 2O, which is actually an oxo-centered triangle of Mn(III) with bridging acetates,123 is the alkene concentration and is presumably the reaction loss of a proton from a complexed acetate such as 14
of the Mn(III) enolate 20 with the alkene to give
to give 15.114 118
radical 21 with loss of Mn(II). â-Keto ester radicals
Rapid electron transfer to the oxo- centered metal system gives radical 16, which adds
analogous to 19 do not appear to be intermediates
to the alkene to give 17. The rate of reaction is
in these reactions. If addition of the alkene to the independent of alkene concentration, since the alkene Mn(III) enolate is the rate-determining step, the is not involved in the rate-determining step. Fristad length of the tether should, and does, affect the rate found that the log of the rate of oxidation relative to of oxidative cyclization of unsaturated â-keto esters.
that of acetic acid equals 0.344(∆pK 6-exo-cyclization is more rapid than 5-exo-cycliza- a) for five mono- substituted acetic acids covering an acidity range for tion.19 The nature of the tether also affects the rate -proton of 16 pK of oxidative cyclization of unsaturated â-keto acids.13 Why does the presence of the -alkyl group change the mechanism of the reaction? A methyl group
should slow down the formation of Mn(III) enolate
18, since it is electron donating and decreases the
acidity of the
-proton. On the other hand, the methyl group should facilitate the oxidation of 18 to
19 since it will stabilize the radical. Electrochemical
data for the oxidation of enolates of â-dicarbonyl
compounds to the radical in DMSO support this
The presence of an facilitates the oxidation by 0.25 0.4 V.121,122 The nature of the reaction depends on two variables: therate of formation of the Mn(III) enolate, which 342 Chemical Reviews, 1996, Vol. 96, No. 1
corresponds to the pKa, and the ease of oxidation of of products are sometimes obtained.38 The use of the enolate to give a free radical. For most com- ethanol can be advantageous in cyclizations to alkynes.
pounds enolization is the rate-determining step. For Vinyl radicals formed by cyclization to alkynes are very acidic compounds such as not readily oxidized by Mn(III) and will undergo â-keto esters and â-diketones, enolization occurs undesired side reactions unless there is a good readily and oxidation is slow.
hydrogen donor available. Ethanol acts as a hydro-gen donor, reducing the vinyl radical to an alkeneand giving the -hydroxyethyl radical, which is oxidized to acetaldehyde by Mn(III). Much higheryields of alkenes are obtained from cyclizations toalkynes in ethanol than in acetic acid.28 â-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with 2O is not particularly expensive on a laboratory scale, but its use on an industrial 3 at room temperature or slightly above.24 They may be cyclic or acyclic and may be scale may be problematic.
Several groups have stituted or may contain an -alkyl or chloro substitu- demonstrated that Mn(III) can be used in catalytic ent. Cycloalkanones are formed if the unsaturated quantities and regenerated electrochemically in chain is attached to the ketone. γ-Lactones are In some cases, good yields of formed from allylic acetoacetates.48,49,51 Less acidic products are obtained with only 0.2 equiv (10%) of â-keto amides have seen limited use for the formation Mn(III) or Mn(II). In other cases the electrochemi- of lactams71 or cycloalkanones.40 Malonic esters have cally mediated reactions proceed in substantially also been widely used and form radicals at 60 80 lower yield or give different products. D'Annibale °C. Cycloalkanes are formed if an unsaturated chain and Trogolo have recently reported that improved is attached to the -position.
yields are obtained in some Mn(III) and Ce(IV) based γ-Lactones are formed oxidative cyclizations and additions if they are car- from allylic malonates.41,48,49,51 â-Diketones have ried out with ultrasound irradiation.89 91 been used with some success for cyclizations to bothalkenes and aromatic rings.24,98,101,102 Other acidic Mn(OAc)3 is also involved in the termination step.
carbonyl compounds such as â-keto acids,13 â-keto It rapidly oxidizes tertiary radicals to cations that sulfoxides,27 â-keto sulfones,27 and â-nitro ketones105 lose a proton to give an alkene or react with acetic have seen limited use.
acid to give acetate esters. Mn(OAc)3 oxidizes allylicradicals to allylic acetates and oxidizes cyclohexadi- Although Mn(III)-based oxidative additions of enyl radicals generated by additions to benzene rings acetic acid have been widely used,8 11 to cations that lose a proton to regenerate the cyclizations of unsaturated acids have not been aromatic system. On the other hand, Mn(OAc) successfully carried out, because the solvent acetic oxidizes primary and secondary radicals slowly, so acid is oxidized as readily as the substrate. We have that hydrogen atom abstraction from solvent or recently found that oxidative cyclizations of unsatur- starting material becomes the predominant process.
ated ketones can be carried out in high yield in acetic Alkenes are formed efficiently from primary and acid at 80 °C if the ketone selectively enolizes to one secondary radicals by use of Cu(OAc)2 as a cooxidant, side and the product cannot enolize. These reactions as discussed in section III.
are discussed in detail in section IX.
Narasaka introduced manganese(III) picolinate [Mn(pic)3] in DMF as a useful reagent for oxidation C. Oxidants
of â-keto acids to radicals, the oxidative cleavage ofcyclopropanols to give â-keto radicals, and the oxida- tion of nitroalkanes to cation radicals.77 81 different results are obtained from oxidation of â-keto
acid 22 with Mn(OAc) 2H
Commercially available Mn(OAc) 2O and Mn(pic)3.
tion with Mn(pic) used for the majority of oxidative cyclizations. This 3 in DMF results in decarboxylation -keto radical 23 as shown in eq 7.
reagent can also be prepared easily from potassium permanganate and manganous acetate in acetic acid.8Anhydrous Mn(OAc)3 is slightly more reactive thanthe dihydrate. Reaction times with the anhydrousreagent are usually somewhat shorter but the yieldof products are usually comparable. Both trifluoro-acetic acid and potassium or sodium acetate havebeen used with Mn(OAc)3. Use of trifluoroacetic acidas a cosolvent usually increases the rate of thereaction, but often decreases the yield of products.
Acetate anion may accelerate enolization and act asa buffer.
Acetic acid is the usual solvent for Mn(OAc)3 2H Radical 23 adds to enol silyl ethers to give good yields
reactions. DMSO, ethanol, methanol, dioxane, and of 1,4-diketones and to -methylstyrene to give a low acetonitrile can also be used, although higher reac- yield of addition products. Oxidation of 22 with Mn-
tion temperatures are required and lower yields (OAc)3 in DMF leads to dimers and trimers and Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 343
â-keto acid radical 24 that adds to
(III) carboxylates could be prepared from Mn(OAc) to give 6% of the lactone shown in eq 8. There are and the carboxylic acid in situ and used for acyloxylation of enones and aryl alkyl ketones.128 133 The utility of these manganese(III) carboxylates inoxidative free-radical cyclizations has not been ex-amined.
2. Ce(IV), Fe(III), V(V), etc.
A wide variety of other one-electron oxidants have been used for generating free radicals, especially forthe oxidative coupling of phenols.11 Hirao et al. haveused VO(OEt)Cl2 to generate radicals from diketenein ethanol.135 Kende has shown that alkaline potas- several structural differences that may be responsible sium ferricyanide induces oxidative cyclization of for the distinct reactions observed with these two phenols with a side chain bearing a nitro group or a reagents. The nitrogen of the picolinate coordinates readily enolizable carbonyl group (eqs 9 and 10).136 139 to manganese, perturbing the oxidation potential.124Mn(pic)3 has an octahedral manganese, with threepicolinates bound to a single Mn(III),125 whileMn(OAc)3 is an oxo-centered trimer.123 We examined the tandem oxidative cyclization of 25 with various Mn(III) reagents and Cu(OAc)2.38
Oxidative cyclization with Mn(OAc)3 and Cu(OAc)2
affords 86% of 27 and 0% of 28, while use of Mn(pic)3
and Cu(OAc)2 leads to 0% of 27 and 15% of 28. A
series of control experiments established that the
most likely explanation for this observation is that
Mn(pic)2, but not Mn(OAc)2, reacts with the bicyclic
radical 26 more rapidly than Cu(OAc)2 does. This
illustrates a general feature of oxidative radical
cyclizations. A one-electron oxidant, e.g., Mn(III),
Cu(II), Ce(IV), etc., is needed for both the generation
of the acyclic radical and oxidation of the cyclic
radical. Furthermore, the lower valent metal salt
produced in these oxidations must not react rapidly
with any of the radical intermediates. Mn(pic)3 does
not meet these requirements, since Mn(pic)2 reacts
with the cyclic radical more rapidly than Cu(OAc)2
These reactions probably proceed by oxidation to the does; the alkylMn(pic)2 intermediate produced in this radical, cyclization to the radical anion, and further reaction apparently abstracts a hydrogen giving oxidation as shown in eq 10. Analogous reactions reduced products such as 28.
have also been carried out with Mn(OAc)3 in a modelstudy for fredericamycin A.98 Citterio and co-workers have comprehensively ex- plored the use of ferric perchlorate in acetonitrile foroxidative intermolecular additions of malonate estersto styrenes and oxidative cyclizations of unsaturatedmalonate esters and compared this reagent toMn(OAc) 3 and ceric ammonium nitrate.58,61,63,64,67- Co(OAc)2 and molecular oxygen in acetic acid havebeen used for the oxidative addition of â-diketonesand â-keto esters to alkenes. The oxidant is probablyCo(III), and the addition product is trapped withoxygen, leading to a dihydrofuran analogous to thatformed in eq 4.140 142 Baciocchi and co-workers have used ceric ammonium nitrate to oxidize malonate Mn(AcAc)3 and MnF3 are other readily available esters to radicals in alcohol solvents.119,143 The utility Mn(III) reagents. Mn(AcAc)3 has been extensively of ceric ammonium nitrate for oxidative cyclization used for oxidative coupling of phenols.126 While both of malonate esters and â-keto esters to aromatic are suitable for oxidative radical cyclizations, they systems has been examined by Citterio and co- appear to offer no advantages over Mn(OAc) Watt and Demir127 133 have comprehensively devel- All of these oxidants are capable of forming radicals ′-oxidation of enones to ′-acyloxyenones from 1,3-dicarbonyl compounds. However, the oxi- discovered by Hunter.134 During the course of this dant is also necessary for termination of the radical work they found that a wide variety of manganese- The nature of the metal, the ligands 344 Chemical Reviews, 1996, Vol. 96, No. 1
necessary to obtain the desired oxidation potential, expense of lactone 35 (13%). Oxidative cyclization
and the solvent needed to achieve solubility of the of 29 with 2 equiv of both ceric ammonium nitrate
metal salt all play a crucial role in determining the and Cu(BF4)2 affords 86% of lactone 35 in acetic acid
products formed from oxidation of the cyclic radical.
and 81% of nitrate 39 in acetic acid containing acetic
The choice of oxidant is less important in reactions that are terminated by addition to an aromatic ring.
The oxidation of 29 with different oxidants dem-
The aromatic system will inevitably be regenerated onstrates that the major differences are in the in high yield by oxidation of the cyclohexadienyl termination step. All oxidants give radical 30, which
radical to the cation and loss of a proton.
cyclizes to a ∼9:1 mixture of 33 and 31. The
The differences in termination are clearly seen in oxidative termination step is oxidant, ligand, and the oxidative cyclization of diethyl 4-pentenylma- solvent dependent.
lonate (29), which has been investigated with Ce(IV),
Fe(III), and Mn(III). Oxidative cyclization of 29 with
2 equiv of Mn(OAc)3 2H
D. Further Oxidation of the Product
and 1 equiv of Cu- 2O in acetic acid at 55 °C gives 48% of lactone 35, 20% of methylenecyclopentane 34, and
Oxidative cyclization of unsaturated â-dicarbonyl 7% of cyclohexene 32.28,29,38 Oxidation of 29 gives
compounds that have two -hydrogens will give radical 30, which cyclizes to a 9:1 mixture of cyclo-
products that still have one -hydrogen and can be pentylmethyl radical 33 and cyclohexyl radical 31,
oxidized further. These reactions can be divided into as has been observed in atom transfer cyclizations.144 three categories, depending on whether the product Oxidation of 31 with Mn(III) or Cu(II) gives 32;
is oxidized more slowly, at about the same rate, or oxidation of 33 with Cu(II) gives 34 and 35. The ratio
much faster than the starting material. In the first of 35 and 34 is solvent dependent, ranging from as
category, the product is oxidized more slowly than high as 3.75:1 in acetonitrile to as low as 0.04:1 in the starting material, so that the cyclization proceeds DMSO, with intermediate values in AcOH (2.4:1), in good yield. The formation of 71% of 13a from 8a
EtOH (0.64:1), DMF (0.55:1), and MeOH (0.48:1).
is an example of this type of reaction.14,24 In the second category, the product is oxidized at a rate competitive with that of the starting materialso that mixtures of products are obtained.
instance, oxidative cyclization of 41a gives the ex-
pected product 42a in only 21% yield, while 41b
affords 36% of 42b and 10% of dienone 44b formed
by further oxidation of 42b. Competitive oxidation
of the product is usually not a problem in intermo-
lecular addition reactions because a vast excess of
the oxidizable substrate, such as acetone or acetic
acid, is usually used as solvent.
substrate is not possible in oxidative cyclizations.
Oxidation of 29 with Fe(ClO4)3 9H
2O in acetonitrile at 20 °C affords 7% of 32, 4% of 34, 44% of 35, 7% of
the reduction product 37, 10% of alcohol 36, and 6%
of amide 38, which results from reaction with aceto-
nitrile. The last three products were not observed
with Mn(OAc)3 and Cu(OAc)2.
Oxidation of 29 with 2 equiv of ceric ammonium
nitrate in methanol affords 20% of lactone 35, 23%
of nitrate 39, 10% of methylenecyclopentane 34, 12%
of reduction product 37, and 6% of cyclohexene 32.143
The rate-determining step in the cyclization of The formation of nitrate is suppressed using 2 equiv -unsubstituted â-keto esters is addition of the of both ceric ammonium nitrate and Cu(OAc)2 in double bond to the manganese enolate. Oxidative methanol, which affords 58% of 35, 25% of 34, and
cyclization of 8a is faster than oxidative cyclization
4% of 32. This product ratio is very similar to that
of 41 since the double bond is better able to partici-
obtained with Mn(OAc)3 and Cu(OAc)2 in acetic acid.
pate in the rate-determining step with a longer However, oxidation of 29 with ceric ammonium
tether. Furthermore, oxidation of 42b to 44b (50%,
nitrate in acetic acid affords 38% of nitro compound 1 day) is much faster than the oxidation of 13b (0%,
40, 35% of 35, 6% of nitrate 39, 2% of 34, and 4% of
6 days). We cannot explain this difference, but note 32. Addition of 0.33 M Ac2O to the reaction mixture
that 42 is ketonic while 13b is enolic. In other cases
favors the formation of nitrate 39 (46%) at the
we have also observed that enolic 1,3-dicarbonyl Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 345
compounds are oxidized slowly by Mn(III) (see 232a
and vinyl groups cis are not formed. The mixture of 56 and 57 was elaborated to avenaciolide (58) by a
In the third category, the product is oxidized much sequence that used an SN2 reaction on the -chloro more readily than the starting material so that none lactone to form the second lactone ring.41 of the initial product is isolated. These reactions may
still be synthetically useful if the products of further
oxidation are monomeric. For instance, oxidative
cyclization of 45 provides 78% of methyl salicylate
(48).17,21,100 Oxidative cyclization gives radical 46;
oxidation of 46 gives 47, probably as a mixture of
double-bond positional isomers. The unsaturated
cyclic â-keto ester 47 is more acidic than 45 and is
rapidly oxidized further by 2 equiv of Mn(III) to give
a cyclohexadienone that tautomerizes to phenol 48.
The overall reaction consumes 4 equiv of Mn(OAc)3.
A. Oxidation by Mn(III)
Mn(III) will oxidize γ-carboxy radicals, e.g. 17, to
γ-lactones 61 regardless of whether the radical is
secondary or tertiary.8 11
Thus, the addition of acetic acid and substituted acetic acids to alkenes to giveγ-lactones is a general reaction for all classes of The oxidative cyclization of crotyl malonate esters alkenes. Mn(III) does not oxidize isolated primary also falls into the third category. Oxidative cycliza- or secondary radicals, so the oxidation of 17 may
tion of 49 affords 50, which is rapidly oxidized to 51.
involve addition of the radical to the carboxylate to Radical 51 gives intractable material if R
give 59, which is readily oxidized to 61, or the
affords 66% of 52 if R
crotyl.49 The lactone group formation of 60 followed by reductive elimination of
makes the -hydrogen of 50 much more acidic170 than
Mn(II) to yield 61.
those of 49 so that product lactone 50 is oxidized
more rapidly than diester 49.
Addition of 1,3-dicarbonyl compounds to alkenes affords isolated radicals that do not contain a proxi- Further oxidation cannot occur if there are no mal manganese carboxylate, e.g., 12 and 26. Mn-
-hydrogens in the product.
(III) will oxidize tertiary radicals to cations that can prevent further oxidation, but cannot then be re- lose a proton to give an alkene or react with solvent -Chloro substituents serve as protecting to give a tertiary acetate. Mn(III) will also oxidize groups preventing further oxidation of the prod- allylic radicals to allylic acetates and cyclohexadienyl uct.19,41,145,146 For instance, cyclopentanonecarboxy- radicals, resulting from addition to aromatic rings, late ester 42a can be prepared easily by oxidation of
to the cation, which loses a proton to regenerate the -chloro â-keto ester 53, giving 54, which cannot be
aromatic system.
oxidized further. Reduction of 54, which can be
Mn(III) does not oxidize primary radicals such as carried out most simply by addition of zinc dust to 26 or secondary radicals such as 12. If no cooxidant
the reaction mixture, affords 42a quantitatively. This
is used hydrogen abstraction is the major pathway.
one-pot procedure converts 53 to 42a in 56% overall
yield.19 We found that
-chlorine substituents also B. Oxidation by Cu(OAc)2
prevent further oxidation of lactones.
cyclization of 55 affords 82% of a 3.1:1 mixture of 56
In the 1960s, Kochi and co-workers demonstrated and 57.41 The other two stereoisomers with the octyl
that Cu(II) reacts rapidly with radicals (∼106 s1 M 1 346 Chemical Reviews, 1996, Vol. 96, No. 1
to give alkylcopper(III) intermediates (see eq 11).
is oxidized to the epoxide by Mn(III) or Cu(II).
â-Hydroxy radicals generated by Pb(OAc)4 oxidativedecarboxylation of â-hydroxy acids are also oxidizedto epoxides by either Pb(IV) or Cu(II) indicating thatthis is a general method for epoxide formation.23 These can react further with loss of Cu(I) to eitherform an alkene by oxidative elimination, transfer aligand to give RCH2CH2X, or form a carbocation.147,148 Oxidative elimination to form alkenes is the preferredpathway from the reaction of copper(II) carboxylateswith primary and secondary radicals. Tertiary, al- Vinogradov and Nikishin reported that oxidation lylic, and other easily oxidized radicals give cations of ethyl acetoacetate with 4 equiv of Mn(OAc)3 and with copper(II) carboxylates. Other Cu(II) salts give excess LiCl in the presence of 1-hexene results in the cations and ligand transfer products with all types formation of dichloride 68.150,151 Chlorination of the
of radicals.
-position prevents further oxidation of the product.
Heiba and Dessau found that the use of Cu(OAc) Unfortunately, the use of chloride is not compatible is compatible with Mn(OAc) with Cu(II); only , -dichlorination is observed. The 3 and that Cu(II) oxidized secondary radicals to alkenes 350 times faster than combination of Mn(OAc)3 and LiCl has seen very Mn(III) does.113 The Cu(I) that is produced in this limited use in intramolecular reactions.19,21,24,25 Oxi- oxidation is rapidly oxidized to Cu(II) by Mn(III) so dative cyclization of 69 with Mn(OAc)3 gives only 17%
that only a catalytic amount of Cu(OAc) of salicylate 73. However, oxidative cyclization of 69
and 2 equiv of Mn(OAc) with 4 equiv of Mn(OAc)3 and 10 equiv of LiCl in 3 are still required.
the course of our studies we observed that, contrary acetic acid at room temperature for 16 h affords a to earlier indications,149 Cu(OAc) mixture containing 48% of 71, 26% of 72, and 6% of
2 oxidizes secondary radicals to give primarily (E)-alkenes and the less salicylate 73. Heating this mixture with 6 equiv of
substituted double bond (Hofmann elimination prod- LiCl in acetic acid at 100 °C for 1 day converts the uct).23 This selectivity is synthetically valuable since mixture to salicylate 73 in 71% overall yield.21
Cu(II) oxidation of primary and secondary radicalsformed in oxidative cyclizations often gives primarilyor exclusively a single regio- and stereoisomer asdetailed below.
Oxidation of primary radicals to alkenes is usually quite efficient as in the conversion of 26 to 27.
However, the organocopper(III) intermediate formed
from primary radicals can interact with adjacent
functionality to give lactones as in the conversion of
33 to 35 discussed above and to give cyclopropanes
as in the conversion of 63 to cyclopropane 64.
Secondary radicals do not usually undergo these side
reactions. For instance, no cyclopropane is formed
from 49, which gives 50, which reacts further as
discussed above.
D. Addition to Nitriles and Carbon Monoxide
We have found that oxidative cyclizations can be terminated by addition to nitriles to give iminylradicals that are reduced to imines, which are Oxidative cyclization of δ-hydroxy â-keto ester 65
hydrolyzed to ketones on workup (see 323 f 325).31
was investigated as a potential route to resorcinols.
Ryu and Alper reported that the radicals formed in To our surprise, the major product isolated in 50 oxidative cyclizations add to carbon monoxide to give 60% yield is the epoxide 67.21 â-Hydroxy radical 66
acyl radicals, which are oxidized by Mn(III) to acyl Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 347
cations leading to carboxylic acids on workup (see eq reaction with Mn(OAc)3, not by intermolecular hy- drogen transfer.
E. Hydrogen Abstraction
Oxidation of radicals by Cu(OAc)2 is sufficiently Reductive termination of the reaction sequence by rapid so that all oxidative cyclizations run in the hydrogen abstraction is occasionally the desired presence of Cu(OAc)2 are kinetically controlled. Since reaction. This is particularly important in converting hydrogen-transfer reactions are much slower, rear- vinyl radicals (obtained from addition to alkynes) to rangement or isomerization of primary or secondary alkenes, since vinyl radicals are not oxidized to vinyl radicals can occur in the absence of Cu(OAc)2. Oxi- cations. The hydrogen can come from the solvent or dative cyclization of 81 with 2 equiv of Mn(OAc)3 and
-hydrogen of another molecule of the 1 equiv of Cu(OAc)2 in acetic acid for 2 days at 55 °C â-dicarbonyl compound. Ethanol is the preferred affords 35% of 84.36 A similar reaction with 2 equiv
solvent for these reactions, since it is a better of Mn(OAc)3 and no Cu(OAc)2 in ethanol affords 35% hydrogen donor than acetic acid. Hydrogen transfer of 85 as a mixture of stereoisomers. Under these
conditions the cyclization of the stabilized radical 82
from ethanol gives the -hydroxyethyl radical that to give 83 is reversible and the more stable cyclohexyl
is oxidized to acetaldehyde by Mn(III) so that these radical 87 is formed. The unstabilized cyclohexyl
reactions still require 2 equiv of Mn(OAc)3.28 radical 87 cyclizes irreversibly to 86, which abstracts
Oxidative cyclization of 74a with Mn(OAc)3 in
a hydrogen atom to give 85. Cyclization of 81 with
acetic acid proceeds in very low yield, giving 9% of a benzoyl peroxide in cyclohexane at reflux under 1:6.3 mixture of 78a and 79a.28 A similar reaction
Julia's conditions also affords 85, contrary to earlier
with anhydrous Mn(OAc)3 in ethanol affords 32% of a 1.6:1 mixture of 78a and 79a. The low yield is
probably due to the instability of methylenecyclopen-
tane 78a. Oxidative cyclization of 74b under the
same conditions provides 66% of a 1:2.6 mixture of
77b and 78b.
Reduction of vinyl radicals to alkenes and primary and secondary radicals to alkanes is also favored bythe use of Mn(pic)3, rather than Mn(OAc)3, as theoxidant.38,39,42 This was discussed in detail in sectionII.C.1.
Cyclizations that form a single carbon carbon bond are systematically surveyed in this section. Thedata are organized according the nature of the ring Oxidative cyclization of 25 with Mn(OAc)3 in acetic
being formed and within that category by the type acid affords radical 26, which abstracts a hydrogen
of dicarbonyl compound. Unsaturated acids 88 are
atom from another molecule of 25 or from solvent to
discussed in section IV.A. The cyclizations of unsat- give 24% of 28.38 We were surprised to find that
urated ketones 89 that lead to cycloalkanones are
oxidation of 80 with an -deuterium under the same
discussed in section IV.B. The cyclizations of conditions affords 65% of 28.38 Large kinetic isotope
esters, â-diketones, and malonate esters 90 that lead
effects change the nature of the termination step so to cycloalkanes are described in section IV.C. All that 26 now abstracts a hydrogen only from the
cyclizations of 91 that lead to lactams or lactones are
solvent and the radical is generated from 80 only by
covered in section IV.D, while all oxidations of 92
348 Chemical Reviews, 1996, Vol. 96, No. 1
involving additions to aromatic rings are presented upial.99 Upial could not be prepared by an analogous in section IV.E.
route because the oxidative cyclization fails with the
epimer with a â-OMOM group and proceeds in only
9% yield with the epimer with a â-methyl group. The
two methyl groups and the MOM ether are equatorial
on the cyclohexene ring of 99 forcing the malonate
side chain to be axial, as required for cyclization. If
either substituent is epimerized the cyclohexene will
flip to the conformation with an equatorial malonate
side chain. In this conformation the radical formed
by oxidation of the half malonate ester probably
undergoes intermolecular reactions before it can
achieve the desired conformation for cyclization.
A. Radicals Derived from Acids
Some of the earliest examples of Mn(III)-based oxidative cyclizations involve â-keto acids, cyanoace-tic acids, and half malonic esters. Since the cyclized B. Radicals Derived from â-Keto Esters and
radical is being oxidized to the lactone, Cu(II) is not â-Diketones That Lead to Cycloalkanones
needed as a cooxidant in these reactions. Coreyreported that the oxidative cyclization of â-keto acid Oxidative cyclizations of â-keto esters that form 93a affords 63% of 94a, while half malonate ester
cycloalkanones have been extensively explored. The 93b provides 64% of bis lactone 94b.13 The oxidative
regiochemistry of the cyclizations is discussed in cyclization of â-keto acid 95 to 96 is much slower (23
order of the length of the tether, which ranges from °C, 24 h) than the cyclization of 93a (23 °C, 20 min),
5-hexenyl to 7-octenyl.
indicating that addition of the double bond to themanganese enolate is the rate-determining step inthese reactions as discussed above in section II.A.
-Unsubstituted â-Keto Esters The oxidative cyclization of -unsubstituted â-keto esters such as 101 proceeds through the cyclization
of the alkene onto the manganese enolate of 102 to
give either 103 or 104 as discussed in section II.A
(see eq 6). 6-endo-Cyclization (n
1) to give 104 is
the exclusive reaction if the proximal carbon is more
highly substituted than the distal carbon. Monosub-
stituted alkenes give cyclohexyl radical 104, which
is oxidized further providing a general synthesis of
salicylate esters (see 45 f 48).17,21,100 Oxidative
cyclization of 101, n
also proceeds exclusively 6-endo although complexmixtures are obtained from oxidation of the radical.21 Fristad reported that oxidative cyclization of cy- anoacetic acid 97a and half malonate ester 97b in
acetic acid at 70 °C provides ∼50% of cyclohexane
lactone 98.15 This procedure gives more complex
mixtures of cyclopentane lactones with a one-carbon-
shorter tether and cannot be used to make cyclohep-
tane lactones.
Oxidative cyclization of 105 with Mn(OAc)3 in
acetic acid in air affords 31% of 1,2-dioxin-3-ol 108.103
6-endo-Cyclization gives cyclohexyl radical 106, which
Paquette reported the oxidative cyclization of 99
reacts with oxygen to give alkylperoxy radical 107,
to afford 68% of 100, which he elaborated to epi-
which abstracts a hydrogen atom to give 108. The
Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 349
analogous formation of 1,2-dioxin-3-ols in intermo- 7-endo- and 8-endo-cyclization occurs exclusively lecular additions of â-dicarbonyl compounds to alk- for 101, n
2,3, if the proximal carbon is more highly enes has been extensively studied.152 158 substituted than the distal carbon. â-Keto esters
117a and 117b afford low yields of 118a and 118b,
since further oxidation of the product is a competing
side reaction.20,30 Both White and Ruveda reported
the oxidative cyclization of 119 to give 120 in 60%
yield.103,106 6-exo-Cyclization occurs exclusively with
1,2-disubstituted alkenes (see 8a f 13a) and with
alkenes in which the distal carbon is more highly
substituted. For instance, 121 affords 41% of 122.14,24
5-exo-Cyclization is the exclusive reaction with 1,2- disubstituted alkenes (see 41 f 42) or if the distal
carbon is more highly substituted. Oxidative cycliza-
tion of 109 with Mn(OAc)3 2H
2O affords 10% of acetate 110 and 8% of alkene 111. The low yield is
due to the further oxidation of the products. The
cyclized radical is oxidized to a cation, which loses a
proton to give alkene 111 or reacts with solvent to
give acetate 110. Similar mixtures are obtained if
Cu(OAc)2 is used as a cooxidant, since Cu(II) also
oxidizes tertiary radicals to alkenes. Oxidative cy-
clization of 112 with Mn(OAc)3 2H
yields 49% of 114 as a 3:2 mixture of stereoisomers.
Use of Cu(OAc)2 as a cooxidant is necessary indicat-
ing that the electron-withdrawing chlorine group
prevents oxidation of radical 113 to the cation by Mn-
-Substituted â-Keto Esters (III) or Cu(II), allowing clean conversion to 114 by
oxidative elimination with Cu(II).19 The oxidative cyclization of -substituted esters such as 123 proceeds through the formation of free
radical 124, which cyclizes to give either 125 or 126
as discussed in section II.A (see eq 5).
Oxidative cyclization of styrene 115 with Mn(OAc)3
affords 70% of acetate 116.100 The secondary benzylic
radical that is formed in the cyclization is oxidized
by Mn(III) to the benzylic cation, which reacts with
the solvent to give 116. The improved yield of 116
Oxidative cyclization of monosubstituted alkene as compared to 42 (21%) is probably due to conjuga-
127 with 2 equiv of Mn(OAc)3 and 1 equiv of Cu-
tion of the double bond to the aromatic ring. The rate (OAc)2 affords a mixture of 128 132, which varies
determining step, cyclization of 101, n
as a function of the solvent (acetic acid or ethanol) should be much faster than cyclization of 101, n
and the ester group (OMe or OEt).28 A ∼1:1 mixture Me, while further oxidation of the products of 6-endo/5-exo-products is obtained in acetic acid, should occur at similar rates.
while a ∼1:2 mixture is formed in ethanol. Thiscontrasts with the reaction of the analogous substituted keto ester 45, which gives only products
resulting from 6-endo-cyclization of the manganese
enolate.21 Mixtures of 6-endo- and 5-exo-products are
also obtained from terminal alkyne 74a.28 The pres-
350 Chemical Reviews, 1996, Vol. 96, No. 1
ence of the carbonyl group in the ring being formedfavors the formation of the cyclohexyl radicals ascompared to typical 5-hexenyl radicals, which givealmost exclusively cyclopentylmethyl radicals.1 3 5-exo-Cyclization is the predominant or exclusive reaction with 1,2-disubstituted alkenes 133, 135, and
alkyne 74b.17,24,28 Allylic acetate 137 is formed by
further oxidation of the initially formed 3-cyclohex-
enone. Trisubstituted alkene 138 gives the expected
mixture of alkene 139 and acetate 140, both as
mixtures of stereoisomers. 6-endo-Cyclization is the
exclusive reaction with 123, R1
alkyl, as discussed below in the tandem cyclizations section.
Only 8-endo-cyclization has been observed with 7-octenyl radicals.20,30 Alkene 141c provides 47% of
142c, while 141d affords 38% of 142d. The corre-
sponding alkyne 147b provides 34% of 8-endo-
product 148b. Finally, cyclization of 1,1-disubstitut-
ed alkene 151b yields 69% of a mixture of 8-exo-
cyclization products 152b and 153b.
a. Stereochemistry of 6-endo- and 6-exo-Cycliza- tions. Radicals 154 and 160 cyclize through the
conformations shown with the ester group oriented
anti to the ketone. This is most clearly established
by analysis of the products derived from 6-endo- and
6-exo-cyclizations. The cyclohexane ring is formed as
a chair in both classes of cyclizations. 6-exo-Cycliza-
tion of cis-alkenyl radical 154a gives a ∼20:1 mixture
Cyclization of monosubstituted alkene 141a affords
of radicals 155 and 156, while trans-alkenyl radical
50% of 7-endo-cyclization product 142a and 18% of
154b gives a 3:1 mixture of the same two radicals.
6-exo-cyclization product 143a.20,30 Analysis of the
Steric hindrance between the axial ring hydrogen more complicated mixtures of products obtained from shown and R1 destabilizes transition state B leading
141b indicates that cyclization gives a ∼2.5:1 mixture
to 156. This interaction becomes more severe as R1
of cycloheptyl and cyclohexanemethyl radicals. Simi- increases in size resulting in much greater selectivity lar results are obtained with cyclic keto ester 144
for 155 from the cis alkenyl radical 154a. Radicals
which gives 35% of a 1:1 mixture of 145 and 146.24
155 and 156 are oxidized by Cu(II) to alkenes 157-
The corresponding alkyne 147a affords only 7-endo-
159 in the yields shown (from 154a and 154b,
product 148a in 35% yield.
Cyclization of 1,2- respectively). The selective formation of the least disubstituted alkenes results in exclusive 6-exo- substituted double bond as the trans-isomer is a cyclization (see 8b f 13b and 162 f 163
general property of Cu(OAc) 2 oxidation of secondary Similarly, 6-exo-cyclization is observed with alkyne radicals.23 The cyclization of 160 has been shown to
149. On the other hand, cyclization of 1,1-disubsti-
proceed through the chair transition state to give 161
tuted alkene 151a affords 69% of the 7-endo-cycliza-
in studies of tandem cyclizations discussed below.
tion products 152a and 153a.
Oxidative cyclization of cyclic â-keto ester 162 also
Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 351
proceeds through a chair transition state with an C. Radicals Derived from â-Keto Esters,
equatorial double bond affording 78% of 163 and only
â-Diketones, and Malonate Esters That Lead to
4% of 164 with the more substituted double bond.
Radical 173, which forms a cycloalkane rather than
a cycloalkanone, shows the normal preference for
5-exo-cyclization to give 174 instead of 6-endo-cy-
clization to give 175. With monosubstituted alkenyl
radicals (173, R1, R2
H) a 9:1 mixture of 5-exo-/6- endo-cyclization products are obtained (see 29). 1,2-
Disubstituted alkenyl radicals (173, R1
alkyl) undergo exclusively 5-exo-cyclization (see 81).
Acetoacetate 176 affords 67% of a 7:3 mixture of 177
and 178.24 On the other hand, 6-endo-cyclization still
occurs exclusively with trisubstituted alkenes (173,
R1, R2
alkyl).16 Rama Rao reported a very unusual 5-endo-cyclization of indandione 179 that gives 72%
of 180 in a model study for the synthesis of frederi-
Oxidative cyclization of a series of 4-alkenyl-2- methylcyclopentane-1,3-diones proceeds in moderate
yield to give 6-endo- and 7-endo-cyclization prod-
ucts.24 For instance, 165 affords 38% of 166 and 7%
of 167, while 168 gives 34% of a 1:1 mixture of 169
and 170. Oxidative cyclization of cyclohexane-1,3-
dione 171 affords 88% of a mixture of all four
stereoisomers of 172, all of which have been used for
the total synthesis of upial.46
D. Radicals Derived from â-Keto Esters, â-Keto
Amides, and Malonate Esters That Lead to
Lactones and Lactams

Oxidative cyclization of allylic malonates and ac- etoacetates has been developed as a general route toγ-lactones by 5-exo-cyclizations.24,41,47 49,51 no reports of 6-endo-cyclization even with a 1,1-
disubstituted double bond (see 182b). Except for a
single example of 6-exo-cyclization there are no
reports of the formation of δ- or larger lactones.24
Bertrand found that oxidative cyclization of 63
provides 42% of cyclopropane 64.47 49
acetoacetate affords 57% of the cyclopropane.48 We
obtained modest yields of γ-lactone 181a and δ-lac-
tone 181b.24 The products are probably oxidized
further as observed in the oxidative cyclization of
crotyl malonate 49.49 Further oxidation is prevented
by use of the -chloromalonate (see 55
352 Chemical Reviews, 1996, Vol. 96, No. 1
-methyl malonates 182 undergo 5-exo-
cyclizations can also be carried out with ceric am- cyclization to give the radical which undergoes the monium nitrate and ferric perchlorate.58,67,95 Oxida- expected oxidative termination to give mixtures of tive cyclization of 5-aryl-3-oxopentanoates 196 with
alkenes, lactones, and acetates depending on the ceric ammonium nitrate in methanol leads to 2-hy- substitution pattern.47 49 droxy-1-naphthoate esters 199 in 30 60% yield.62
Mn(OAc)3 in acetic acid is usually less effective for
these cyclizations. Dihydrotetralin 201 and cyclo-
propanes 202 are formed by oxidative cyclization of
cinnamyl malonate 200 with Mn(OAc)3 in acetic acid
at 60 °C.68 The double bond apparently isomerizes
by reversible cyclization to the cyclopropylcarbinyl
radical precursor of 202.
Cossy reported the oxidative cyclization of N,N-bis- (allyl) and N-propargyl â-keto amides 187 and 189
with Mn(OAc)3 in EtOH for 1 h at room temperature
to give good yields of γ-lactams 188 and 190.71,73
Under these conditions, in EtOH and in the absence
of Cu(II), the cyclized radicals abstract a hydrogen
from the solvent.28
E. Additions to Aromatic Rings
Oxidative cyclization of acylpyrrole 203 with Mn-
Citterio comprehensively explored the Mn(OAc)3- (OAc)3 in acetic acid at 80 °C affords a quantitative induced oxidative cyclization of -arylalkylmalonate yield of ketorolac precursor 204.96 Oxidative cycliza-
esters.58,60,62,67,68 Oxidative cyclization of 191 in acetic
tion of 205 with Mn(OAc)3 in acetic acid at 100 °C
acid at 80 °C affords 80 88% of 192.60 The reaction
gives 32% of 206, a model for the synthesis of
tolerates methoxy, acetamido, and nitro substituents fredericamycin.98 Oxidative cyclization of chloroac- on the aromatic ring. The reaction can be used for etamide 207 with Mn(OAc)3 2H
2O in acetic acid at formation of chroman 193 and phenanthrene 194.60
50 °C yields 21% of â-lactam 208 which is formed by
Indan 195 is formed in modest yield.60
Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 353
radical with Cu(II) is much faster than the second
cyclization, because a relatively strained trans-fused
hydrindan is formed. Similarly, oxidative cyclization
of 218 with Mn(OAc)3 affords 57% of lactone 219 and
20% of lactone 220.51 If Cu(OAc)2 is used as a
cooxidant, 20% of 219 and 56% of the alkene analo-
gous to 217 are formed.
V. Tandem Cyclizations
More complex targets can be made with excellent stereocontrol by tandem oxidative cyclizations. Thesereactions can be divided into two classes dependingon whether the second cyclization is to an aromatic We found that oxidative cyclization of 221a with 2
ring or to a second double bond.
equiv of Mn(OAc)3 in acetic acid at 15 °C or in MeOH
at 0 °C provides 50 60% of 226a as a single stere-
A. Additions to a Double Bond and then an
oisomer whose structure was established by Clem- mensen reduction to give ethyl O-methylpodocarpate
(227a).14,17,40 Oxidation gives
-keto radical 222a
We have examined three classes of alkene/arene with the ester anti to the ketone. Cyclization occurs tandem cyclizations. The arene can be attached to through a chairlike transition state to give tertiary -carbon as a benzyl group (209, X
radical 223a. The evidence suggest that radical 223a
1, 2),17 to the same chain as the alkene as in 210,14,40
is oxidized to cation 224a, which reacts with the axial
or to the carbonyl group as in 211.17,33,37 Bertrand
ester group to give 225a. A well-precedented Friedel-
has examined cyclizations of 209, X
Crafts alkylation with inversion provides 226a.17 A
form tricyclic lactones.51 similar cyclization of 221b provides 90% of 226b,
suggesting that the oxidation of the electron-rich
aromatic ring is responsible for the lower yield of
226a. This reaction has since been used to prepare
226c, which was converted to margolicin O-methyl
ether,164,165 and 226d, which was converted to trip-
toquinones B and C.166 Similarly, oxidative cycliza-
Oxidative cyclization of 212 with Mn(OAc)3 in
acetic acid at 25 °C provides 83% of 214 as a single
stereoisomer.17 The initial cyclization gives cyclo-
hexanemethyl radical 213 stereospecifically as dis-
cussed above for the formation of 155. The radical
then adds to the aromatic ring to give 214 with an
equatorial methyl group. Oxidative cyclization in the
presence of Cu(OAc)2 affords only 214, indicating that
the second cyclization is much faster than reaction
of 213 with Cu(II). Cyclization of 216 is less stereo-
selective, providing 74% of a 12:2:1 mixture of 215
and two stereoisomers.17 However, oxidative cycliza-
tion in the presence of Cu(OAc)2 provides only 50%
of 217, indicating that reaction of the monocyclic
354 Chemical Reviews, 1996, Vol. 96, No. 1
tion of -unsubstituted â-keto ester 228 provides 70%
experiments indicate that these effects are primarily of 229 with an equatorial ester group resulting from
steric. The chlorine substituent controls the regi- epimerization after cyclization.14 oselectivity of the cyclization by sterically hinderingattack of the radical on the chlorine-bearing double-bond carbon thereby retarding formation of theâ-chloroalkyl radical. The chlorine substituent doesnot electronically accelerate attack on the other endof the double bond to give the -chloroalkyl radical, e.g. 231b.33
Alkynes can also be used in these tandem cycliza- tions, although the products initially formed are
oxidized further.33 Oxidative cyclization of 236a with
4 equiv of Mn(OAc)
Tandem cyclizations can also be terminated by 3 in acetic acid gives 81% of 238.
The initial product 237a is oxidized to the quinone
cyclization to an arene conjugated with a carbonyl methide which reacts with acetic acid to give 238.
group. Oxidative cyclization of either the E- or Oxidative cyclization of silylalkyne 236b with 3 equiv
Z-isomer of 230a with Mn(OAc)3 in acetic acid affords
radical 231a which cyclizes to give 232a with an
3 in acetic acid gives 71% of 239.
initial product 237b undergoes rapid protodesilyla-
equatorial ethyl group in 85% yield.17,33 This reaction tion to give 237, R
H, which is oxidatively dimer- is useful for the synthesis of anthracycline and ized to give 239.
aureolic acid antibiotics, since it can be carried out
without the ethyl group on the side chain. Cycliza-
tion of 230, R
H, is unsuccessful, presumably because 7-endo-cyclization is faster. We were de-
lighted to find that oxidative cyclization of 230b with
Mn(OAc)3 in acetic acid for 15 h at 25 °C affords 79%
of the desired naphthol 233b. Cyclization proceeds
as for 230a to provide 232b, which undergoes slow
loss of hydrogen chloride to give 233b. Similar
cyclizations of methoxy chloroalkenes 234b and 234c
provided 235b and 235c, which were demethylated
with BBr3 to complete the first syntheses of okicenone
and aloesaponol III.37
B. Additions to Two Double Bonds
The utility of tandem oxidative cyclizations is clearly demonstrated in substrates in which both
additions are to double bonds.18,25,28,30,33,35 Oxidative
cyclization of 240a with 2 equiv of Mn(OAc)3 and Cu-
(OAc)2 in acetic acid at 25 °C affords 86% of bicyclo-
[3.2.1]octane 245a. Oxidation affords -keto radical
241, which cyclizes exclusively 6-endo in the confor-
mation shown to afford tertiary radical 242 with an
equatorial allyl group. Chair chair interconversion
provides 243 with an axial allyl group. 5-exo-Cy-
clization of the 5-hexenyl radical of 243 gives 244 as
a 2:1 mixture of exo- and endo-stereoisomers. Oxida-
tion of both stereoisomers of 244 with Cu(II) provides
Chlorine substituents on the alkene are generally The oxidative cyclization 240c was examined as a
useful for controlling the regioselectivity of the cy- model study for gibberellic acid. This reaction fails clization of 5-hexenyl or 6-heptenyl radicals gener- in acetic acid due to the instability of the enol ether, ated by oxidation of an acetoacetate ester or 1,3- but is successful in ethanol, giving 52% of 245c
diketone with Mn(OAc)3 2H containing the complete gibberellic acid CD ring the exclusive process with radicals containing a system.28 This tandem cyclization sequence tolerates chlorine on the distal double bond carbon, while endo- a wide variety of X substituents.25,28 The yield is cyclization is the exclusive process with radicals 2SiMe3 due to competing protode- containing a chlorine on the proximal double-bond silylation and with X H due to competing 5-exo- Intra- and intermolecular competition cyclization of radical 241f.
Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 355
to the double bond to give 258c would be much faster
than addition to the aromatic ring to give 257c in
conformationally unbiased molecules.
The reactive conformation of radical 241 was
determined by placing substituents on the tether.
Bicyclo[3.2.1]octanes containing axial substituents on
the six-membered ring are the major products.25
Oxidation of â-keto ester 240g gives 48% of 245g and
only 9% of the diastereomer with an equatorial
methyl group. The selective formation of the less
stable product 245g requires that the cyclohexyl
trans-Hydrindans can be prepared stereospecifi- radical undergo chair chair interconversion prior to cally from cis-alkenes.25,29 Oxidative cyclization of the second cyclization. Similarly, oxidative cycliza- 259a provides radical 260, which reacts further to
tion of 246 affords 73% of 247 with the substituent
give 64% of trans-fused hydrindan 261. Only 3% of
axial on the six-membered ring.25 Tandem oxidative the cis-fused isomer 263 is formed. The double-bond
cyclizations in which the first cyclization is 7-endo geometry plays an important role in the selectivity or 8-endo can be used for the preparation of bicyclo- as discussed above in the cyclization of radical 154.
[4.2.1]nonane 249a (68%) and bicyclo[5.2.1]decane
The trans-isomer of 259b gives 30% of 261 and 16%
of 263. Oxidative cyclization of enyne 264 affords
bicyclic radical 265, which is oxidized by Cu(II)
selectively to the least substituted alkene 266 in 32%
We examined the oxidative cyclization of γ,γ-bis- (allylic) acetoacetates 250.35 Oxidation and cycliza-
tion affords cyclohexyl radical 251. If X
undergoes chair-chair interconversion to give radical
252, which cyclizes to 255a (40%). 1,3-Diaxial in-
teractions destabilize 252 if X
H so that the second cyclization can only proceed through boat conformers
253 or 254. Boat conformer 253 is calculated to be
Tandem cyclization can also be carried out with 3 kcal/mol more stable than boat conformer 254.
both double bonds in the same chain. Oxidative Therefore, 250b cyclizes only through 253b to give
-unsubstituted â-keto ester 267a
256b even though there are two allyl groups.
affords 44% of 269a, which is isolated as the enol
zyl â-keto ester 250c cyclizes equally through 253c
-Substituted â-keto esters 267b d af-
to give 257c and through 254c to give 258c. Addition
ford 33 50% of 269b d.24,84 The initial cyclization
356 Chemical Reviews, 1996, Vol. 96, No. 1
affords 268 with an axial ester group; the second
and trans to the axial ester group. A third cyclization 5-exo-cyclization provides exclusively the cis-fused and oxidation gives 280. Oxidative cyclization of 281
provides 39% of 283 and 21% of 285. Oxidative
cyclization of 281 affords a ∼2:1 mixture of exo- and
endo-bicyclic radicals 282 and 284 as in the formation
of 244. A third cyclization of 282 followed by Cu(II)
oxidation provides 283. A third cyclization of 284 is
precluded by ring strain so oxidation by Cu(II) yields
Tandem cyclizations leading to decalins give ex- clusively or predominantly the trans-fused ring sys-
tem.16,83 Oxidative cyclization of 270 affords 63% of
271 as a 10:3 mixture of endo- and exo-alkenes.16 The
second, 6-endo-cyclization gives the trans ring fu-
sion.16 Oxidative cyclization of -unsubstituted â-ke-
to ester 272a affords 43% of trans-decalin 273a along
with 12% of cis-decalin 274a.83
ester 272b affords 57% of trans-decalin 273b as the
only product. The second, 6-exo-cyclization gives the
trans ring fusion. Bicyclo[5.3.0]decanes 276a and
277a and bicyclo[6.3.0]undecanes 276b and 277b are
formed by tandem oxidative cyclization of 275.30 The
second, 5-exo-cyclization affords predominantly the
trans-ring fusion because the initial ring is either a
cycloheptane or cyclooctane. This contrasts with the
cyclization of 267 which yields exclusively the cis-
hydrindan 269 because the initial ring is a cyclohex-
Zoretic has developed a very efficient series of triple and tetra cyclizations leading to trans-decalin ring
systems. Oxidative cyclization of 286 affords 35% of
287 as a 2:1 endo- and exo-alkene mixture.88 Simi-
larly, 288 affords 43% of 289.87 The products are
useful for the synthesis of furanoditerpenes. The
tetracyclization of 290a affords 31% of 291a, while
290b provides 23% of 291b.85 These remarkable
tetracyclizations construct four rings affording only
one of 64 possible isomers!
VI. Triple and Higher Cyclizations
We found that triple cyclizations can be carried out in high yield in properly designed systems.25 Oxida-
tive cyclization of 278 gives 70% of 280 as one of eight
VII. Asymmetric Induction
possible stereoisomers. Oxidative cyclization of 278
gives bicyclic radical 279, as in the formation of 261,
The results described above amply demonstrate with the allyl and methylene groups cis to each other that oxidative free-radical cyclizations often proceed Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 357
with excellent control of relative stereochemistry. Wethen turned our attention to using chiral auxiliariesto control the absolute stereochemistry, a topic ofgreat current interest in free-radical chemistry.159 The use of â-keto sulfoxides was very appealing, since the chiral center is adjacent to the radical
center. We were delighted to find that oxidative
cyclization of 292 affords 296 with almost complete
asymmetric induction.27
This is consistent with -keto radical 293, with the carbonyl oxygen anti to
the sulfoxide in an extended conformation, cyclizing
through a chairlike transition state to give cyclohexyl
radical 294. Cyclization should take place with high
selectivity, as shown, from the face of the
radical with the small lone pair rather than the other
face which is blocked by the phenyl group. Chair-
chair interconversion of 294 to give 295, followed by
cyclization of the 5-hexenyl radical and oxidation by
Cu(II) gives 296.
While the ∼100% de in this thing larger than a methyl group, while the radical cyclization is more than satisfactory, the yield is only cyclizes through conformation 305b if the -substitu-
44% as compared to 86% for cyclization of the ent is methyl. Note that the ester group is anti to analogous â-keto ester 245a.
the carbonyl group in both radicals 305a and 305b
as expected from studies discussed above in section
We therefore turned our attention to ester or amide chiral auxiliaries that would proceed with acceptable
de and in better chemical yield. We examined the
cyclization of 297 with the methyl ester of 245a
replaced with chiral auxiliaries. The reactions pro-
ceed in high yield but modest de (23 60%), with the
exception of the ( )-phenylmenthyl ester 297 which
cyclizes to 299 in 90% yield with 86% de.34,40 The
Oxidative free-radical cyclizations can also be used direction of asymmetric induction is consistent with for annulationsstandem free-radical reactions in the cyclization of radical 298 from the top face in the
which the first carbonscarbon bond is formed by conformation shown. 2,5-Dimethylpyrrolidine amide intermolecular addition and the second is formed by 300 cyclizes to 302 in even higher de (92%) but in
cyclization. We found that oxidation of diethyl al- only 28% yield, a result typical of oxidative cycliza- lylmalonate (306) in the presence of an alkene leads
tions of â-keto amides.34,40 The direction of asym- to radical 307, which undergoes a 5-exo-cyclization
metric induction is consistent with the cyclization of to give a cyclopentylmethyl radical that is oxidized radical 301 from the bottom face in the conformation
by Cu(II) to 308 in the yields indicated.22,53 The
shown. Zoretic reported that the oxidative cyclization
of the camphor sultam â-keto imide analogous to
267a proceeds in 49% yield with 50% de.86
We next applied this reaction to the synthesis of ( )-podocarpic acid.40 To our surprise, oxidative cyclization of 303 affords a 10:1 mixture (82% de)
favoring the natural diastereomer 304. This indi-
cates that the reactive conformation of the radical
obtained from 303 is not the same as that of radical
298. After further experiments we concluded that
the radical cyclizes through conformation 305a if the
-substituent is propyl, allyl, and presumably any- 358 Chemical Reviews, 1996, Vol. 96, No. 1
reaction is synthetically useful with 1,1-di- and N-aroylindole 321 is an example of a different class
monosubstituted alkenes and works better if the of oxidative annulations resulting from two succes- alkene is used in large excess. Oxidative addition of sive radical reactions rather than a tandem addi- diethyl crotyl malonate (309) proceeds similarly to
tion cyclization. The malonyl radical adds to the give cyclic radical 310, which is oxidized by Cu(II)
indole ring; the resulting product is oxidized a second selectively to the least substituted alkene 311.22,53
time and adds to the aroyl group to give 322.55
Citterio reported the oxidative annulations of di- ethyl benzylmalonate (312) with alkenes to give
tetrahydronaphthalenes 314 as shown for 1-octene.63,70
We have examined the termination of both tandem The reaction tolerates a wide variety of substituents cyclizations and annulations by addition to nitrile on both the alkene and aromatic ring. Tetrahydro- groups.31 In a typical example, (cyanomethyl)ac- quinolines 315 are obtained from 2-pyridylmalonates
etoacetate 323 adds to methylenecyclopentane to give
and tetrahydroisoquinolines 316 are obtained from
a radical that undergoes 5-exo-cyclization to the 4-pyridylmalonates; mixtures of products are ob- nitrile group to give imino radical 324. Hydrogen
abstraction and hydrolysis of the imine provides
tained from 3-pyridylmalonates.64 Mn(III), Ce(IV), or Fe(III) can be used as the oxidant in all of thesereactions, which are terminated by oxidation toregenerate the aromatic ring.
analogous annulations leading to indoles 317 and
thiophenes 318.56 Citterio has shown that alkynes
can be used. Oxidative annulation of diethyl ben-
zylmalonate (312) with 1-octyne and Mn(OAc)3 af-
fords 92% of dihydronaphthalene 319.65,70
IX. Oxidation of Ketones
All of the oxidative cyclizations and annulations described above have been initiated by oxidation ofrelatively acidic compounds, such as 1,3-diketones,acetoacetates, malonates, and ketones. We have recently found that Mn(III)-based
oxidative free-radical cyclization of unsaturated ke-
tones is in fact a versatile synthetic procedure with
broad applicability.45 Reaction of cyclopentanone
326a in HOAc with 2.5 equiv of Mn(OAc)3 and 1
equiv of Cu(OAc)2 H
2O for 1.5 h at 80 °C affords 75% of bicyclo[3.2.1]oct-2-en-8-one 329a and 15% of bicyclo-
[3.2.1]oct-3-en-8-one 330a. At 80 °C, oxidation gives
-keto radical 327a. 6-endo-Cyclization affords radi-
cal 328a, which is oxidized by Cu(II) to give 90% of
a 5:1 mixture of 329a and 330a. Similar results are
obtained with 326b. Cyclohexanone 326c reacts
more slowly (18 h, 80 °C) giving a similar mixture of
66% of bicyclo[3.3.1]non-2-en-9-one 329c and 7% of
bicyclo[3.3.1]non-3-en-9-one 330c. These reactions
proceed in excellent yield since ketone 326 can
enolize in only one direction and bicyclic ketones 329
and 330 are not susceptible to further oxidation,
because they cannot enolize.
Chuang found that dimethyl benzylmalonate un- If the product ketone enolizes, further oxidation dergoes annulation reactions with naphthoquinone will occur, efficiently providing 4-acetoxy-2-cyclohex- to give 320.57 The addition of dimethyl malonate to
enones.45 Reaction of acetoacetate 331a with 6 equiv
Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 359
selectively generate -keto radicals from ketones that show a kinetic preference for deprotonation on one
side, even if, as with 340, there are
both sides of the ketone.
The conversion of acetoacetate 8b to either prope-
nylcyclohexanone 13b (157) or vinylnorbornanone
342 at different temperatures clearly illustrates the
2O and 1 equiv of Cu(OAc)2‚ difference in reactivity between 1,3-dicarbonyl com- AcOH for 48 h at 80 °C affords 66% of 334a as a 1:1
pounds and ketones. The oxidative cyclization of 8b
mixture of stereoisomers in a net four-electron oxida- at 25 °C to give 13b (56%) as the major product has
tion. Oxidative cyclization of 331 should give 3-cy-
been discussed above; no 342 is obtained at room
clohexenone 332, if cyclization proceeds analogously
temperature.24 On the other hand, oxidation of 8b
to the conversion of 326 to 329. â,γ-Unsaturated
with 4 equiv of Mn(III) and 1 equiv of Cu(II) for 56 h ketone 332 is more acidic than 331 and is rapidly
at 60 °C or 16 h at 80 °C provides 40% of 342 and
oxidized to radical 333, which is oxidized to 334a.171
only 10% of 13b. Oxidation of pure 13b under these
Similar results are obtained with acetoacetate 331b.
conditions provides 75% of 342. At elevated temper-
atures cyclohexanone 13b is oxidized to the
radical, which undergoes a 5-exo-cyclization ste-reospecifically to give a secondary radical, which isoxidized by Cu(II) to afford the less substituteddouble bond.
Oxidative cyclization of 1-methyl-1-allyl-2-tetralone These results vastly extend the scope of Mn(III)- (335) proceeds in good yield, indicating that the ester
based oxidative cyclizations beyond 1,3-dicarbonyl group present in 326 and 331 is not needed for the
compounds. A wide variety of unsaturated ketones success of this sequence. Oxidative cyclization of can now be used as substrates. The formation of 341
cyclopentanone 338 affords 35% of 339, indicating
suggests that kinetically controlled enolization is the -keto radicals generated by this procedure rate-determining step in -keto radical formation.
cyclize onto aromatic rings.
Bicyclic ketones that cannot enolize further areisolated in good yield. Monocyclic ketones that canenolize are oxidized to γ-acetoxyenones.
X. Oxidation of Enol Ethers and Enamines
Oxidative cyclization of δ,- and ,ú-unsaturated enol silyl ethers 343a and 343b with cupric triflate
and cuprous oxide or ceric ammonium nitrate and
sodium bicarbonate in acetonitrile provides the tri-
cyclic ketones 348a and 348b stereoselectively.26,32
These cyclizations proceed by oxidation of 343 to the
cation radical 344, followed by cyclization of 344 to
cation radical 345. This cation radical undergoes a
Oxidation of 2-allylcyclohexanone (340) affords 52%
second cyclization to give cation radical 346, which
of bicyclo[3.3.1]non-2-en-9-one (341). Enolization of
loses the silyl group to give radical 347, which
the ketone should be the rate-determining step.19 undergoes a second oxidation and loses a proton to Since the methylene protons are kinetically more give 348.
acidic than the methine proton, enolization and The advantage of oxidative cyclization of silyl enol oxidation gives the secondary -keto radical selec- ethers rather than ketones is that silyl enol ether 343
tively. This suggests that it will be possible to is oxidized under conditions that do not oxidize the 360 Chemical Reviews, 1996, Vol. 96, No. 1
189.74,75 Oxidation of enamine 355 prepared from
187 and either pyrrolidine or benzylamine in ethanol
with any of a variety of one-electron oxidants affords
cation radical 356 that cyclizes to give cation radical
358, which abstracts a hydrogen from ethanol to give
188 from the pyrrolidine enamine 355a and benzyl
imine 357b from benzyl enamine 355b. Modest
(30%) asymmetric induction is obtained using enam-
ines prepared from
-methylbenzylamine.74 If Cu- (II) is used as the oxidant, cation radical 358 is
oxidized to 359.75
product ketone 348. Oxidation of 349, the ketone
precursor to 343a, with Mn(OAc)3 in acetic acid at
80 °C also affords 348a. However, 348a is not stable
to these conditions and is oxidized to a complex
mixture containing both stereoisomers of 350. The
oxidative cyclization of silyl enol ethers proceeds
through cation radicals, not radicals, with very
different regioselectivity than is observed in radical
Narasaka generated â-keto radicals by oxidative fragmentation of cyclopropanols 360 with Mn(pic)3
Oxidation of siloxycyclopropane 351 with Cu(BF4)2
in DMF.79,81 The manganese(III) alkoxide 361 frag-
generates cation radical 352, which cyclizes to 353,
ments to give the most substituted radical 362, which
which is oxidized to give 21% of cyclopentane 354.
adds to silyl enol ether 363 to give diketone 364 after
This suggests that cation radicals are intermediates oxidation. The reaction has been extended to cycliza- in the oxidative dimerization of siloxycyclopropanes
with Cu(BF4)2.160 Ryu has found that the intermedi-
ates prepared by treatment of silyloxycyclopropanes
with Cu(BF4)2 add to dimethyl acetylenedicarboxylate
and suggests that organocopper(II) intermediates
such as 351a are formed and add to the triple bond.161
Cation radical 352 is probably formed by electrophilic
ring opening of the cyclopropane with Cu(II) to give
organocopper(II) intermediate 351a, which loses Cu-
(I) to give 352. Iwata has generated cation radicals
tions by using unsaturated cyclopropanol 365.80
that cyclize onto enol ethers by oxidation of cyclo- Reaction of 365 with 2.4 equiv of Mn(pic)3 in DMF
propyl sulfides with ceric ammonium nitrate.169 and 2.5 equiv of 363 affords radical 366, which
cyclizes to give 367, which then reacts with 363 to
afford diketone 368 stereoselectively. Alternatively,
radical 367a can be trapped with Bu3SnH to give
369a, X
H (75%), with diphenyl diselenide to provide 369a, X
PhSe (68%), or with acrylonitrile and Bu3SnH to give 369a, X
Narasaka synthesized 10-isothiocyanotoguaia-6-ene
(370) using this fragmentation cyclization as the key
Booker-Milburn reported analogous cyclizations with FeCl3 leading to chloroketones.162,163 Reaction
of 371a or 371b with FeCl3 in DMF affords radical
367, which reacts with FeCl3 to provide 372a (64%)
or 372b (48%) with a trans ring fusion. The bicyclic
Cossy has examined oxidative cyclizations of the radical 367a abstracts a hydrogen from the solvent
enamines prepared from â-keto amides 187 and
to give 47% of 369a if Fe(NO3)3 9H
2O is used as the Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 361
radical 388, which abstracts a hydrogen to give 45%
of 389.
oxidant. Reaction of bicyclo[3.1.0]hexane 373 affords
51% of perhydroindan 374 with a cis ring fusion.
Fragmentation cyclization of silylalkyne 375 yields
51% of chloroalkene 376.
Oxidative fragmentation sequences are also suc- cessful when the double bond is not conjugated to the
ketone produced in the fragmentation. Oxidation of
390 with Mn(OAc)3 and Cu(OAc)2 in ethanol at 25
°C affords 56% of unsaturated spirocyclic ketone 392
as the major product.39 We used the oxidative frag-
We developed a Mn(III)-based oxidative fragmen- mentation cyclization of ethynylcyclobutanol 393 to
tation cyclization sequence that converts vinyl- and give 58% of methylenecyclopentanone 394 as the key
step in efficient seven-step syntheses of ( )-silphip- and 2-cyclohexenones.39 Oxidation of a vinyl cyclobu- erfol-6-ene (395) and ( )-methyl cantabradienate
tanol such as 377 with Mn(III) gives tertiary radical
378 that undergoes 5-exo-cyclization to yield 379,
which is oxidized by Cu(II) to give 2-methylenecy-
clopentanone 380. Rearrangement of â-keto radical
379 via the cyclopropyloxy radical affords â-keto
radical 383, which is oxidized by Cu(II) to give
cyclohexenone 382. 6-endo-Cyclization of 378 pro-
-keto radical 381, which is not oxidized and
instead dimerizes or abstracts a hydrogen atom to
give the saturated ketone. 2-Methylenecyclopen-
tanones are produced selectively from some vinyl
cyclobutanols, such as 384, which yields 83% of 386.
XII. Synthetic Applications
Other cyclobutanols, including 377, form complex
The reactions discussed above demonstrate the mixtures of products. We therefore developed an synthetic potential of Mn(III)-based oxidative cycliza- alternate route to 2-methylenecyclopentanones from tions and annulations. The starting materials are ethynylcyclobutanols. Oxidative fragmentation and readily available by alkylation of the mono- and cyclization of 387 with Mn(III) affords â-keto vinyl
dianions of â-dicarbonyl compounds. Mono, tandem, 362 Chemical Reviews, 1996, Vol. 96, No. 1
triple, and tetra cyclizations proceed in high yield (19) Snider, B. B.; Patricia, J. J.; Kates, S. A. J. Org. Chem. 1988,
with excellent and predictable control of the regio- 53, 2137.
(20) Merritt, J. E.; Sasson, M.; Kates, S. A.; Snider, B. B. Tetrahedron and stereochemistry. Oxidative termination with Lett., 1988, 29, 5209.
(21) Snider, B. B.; Patricia, J. J. J. Org. Chem. 1989, 54, 38.
2 inserts a double bond into the product regiospecifically producing highly functionalized, poly- (22) Snider, B. B.; Buckman, B. O. Tetrahedron 1989, 45, 6969.
(23) Snider, B. B.; Kwon, T. J. Org. Chem. 1990, 55, 1965.
cyclic products from simple, acyclic â-dicarbonyl (24) Kates, S. A.; Dombroski, M. A.; Snider, B. B. J. Org. Chem. 1990,
substrates. Our recent work showing that oxidative 55, 2427.
cyclizations of simple ketones are synthetically useful (25) Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem. Soc. 1990, 112, 2759.
under a wide variety of circumstances should signifi- (26) Snider, B. B.; Kwon, T. J. Org. Chem. 1990, 55, 4786.
cantly increase the scope of oxidative cyclization.45 (27) Snider, B. B.; Wan, B. Y.-F.; Buckman, B. O.; Foxman, B. M. J. Org. Chem. 1991, 56, 328.
Although the first oxidative free-radical cycliza- (28) Snider, B. B.; Merritt, J. E.; Domboski, M. A.; Buckman, B. O.
tions were reported only a decade ago, the reaction J. Org. Chem. 1991, 56, 5544.
has already been used extensively in total synthesis.
(29) Curran, D. P.; Morgan, T. M.; Schwartz, C. E.; Snider, B. B.; Dombroski, M. A. J. Am. Chem. Soc. 1991, 113, 6607.
Specific examples of natural product syntheses using (30) Snider, B. B.; Merritt, J. E. Tetrahedron 1991, 47, 8663.
oxidative cyclization as a key step include the prepa- (31) Snider, B. B.; Buckman, B. O. J. Org. Chem. 1992, 57, 322.
ration of aloesaponol III (from 235c),37 avenaciolide
(32) Snider, B. B.; Kwon, T. J. Org. Chem. 1992, 57, 2399.
(33) Snider, B. B.; Zhang, Q.; Dombroski, M. A. J. Org. Chem. 1992,
(58),38 a dihydro derivative of pallascensin D (from
57, 4195.
120),106 epi-upial (from 100),99 fredericamycin models
(34) Snider, B. B.; Zhang, Q. Tetrahedron Lett. 1992, 33, 5921.
180101 and 206,103 furanoditerpenes (from 287 and
(35) Dombroski, M. A.; Snider, B. B. Tetrahedron 1992, 48, 1417.
(36) Snider, B. B.; Armanetti, L.; Baggio, R. Tetrahedron Lett. 1993,
289),87,88 the gibberellic acid CD ring system 245c,28
34, 1701.
(37) Snider, B. B.; Zhang, Q. J. Org. Chem. 1993, 58, 3185.
isokuomidine,167 okicenone (from 235b),37 ( )- and
(38) Snider, B. B.; McCarthy, B. A. J. Org. Chem. 1993, 58, 6217.
(39) Snider, B. B.; Vo, N. H.; Foxman, B. M. J. Org. Chem. 1993, 58,
( )-podocarpic acid (227),40 margolicin O-methyl
ether (from 226c),164,165 triptoquinones B and C (from
(40) Zhang, Q.; Mohan, R. M.; Cook, L.; Kazanis, S.; Peisach, D.; 226d),166 silphiperfol-6-ene (395),42 methyl cantabra-
Foxman, B. M.; Snider, B. B. J. Org. Chem. 1993, 58, 7640.
(41) Snider, B. B.; McCarthy, B. A. Tetrahedron 1993, 49, 9447.
dienate (396),42 upial (from 172),46 and aryl tetralin
(42) Vo, N. H.; Snider, B. B. J. Org. Chem. 1994, 59, 5419.
lignans.118 Over the past decade, oxidative free- (43) Snider, B. B.; McCarthy, B. A. In Benign by Design, Alternative radical cyclization has been developed into a broadly Synthetic Design for Pollution Prevention; Anastas, P. T., Ferris,C. A., Eds; ACS Symposium Series 577; American Chemical applicable synthetic method. Although further de- Society: Washington, DC, 1994; pp 84 97.
velopment is needed, the scope, limitations, and (44) Snider, B. B.; Han, L. Synth. Commun. 1995, 25, 2357.
mechanism of these reactions are sufficiently well (45) Snider, B. B.; Cole, B. M. J. Org. Chem. 1995, 60, 5376.
(46) Snider, B. B.; O'Neil S. Tetrahedron 1995, 51, 12983.
understood that they can be used predictably and (47) Surzur, J. M.; Bertrand, M. P. Pure Appl. Chem. 1988, 60, 1659.
reliably in organic synthesis.
(48) Oumar-Mahamat, H.; Moustrou, C.; Surzur, J.-M.; Bertrand, M.
P. Tetrahedron Lett. 1989, 30, 331.
(49) Oumar-Mahamat, H.; Moustrou, C.; Surzur, J.-M.; Bertrand, M.
P. J. Org. Chem. 1989, 54, 5684.
(50) De Riggi, I.; Surzur, J.-M.; Bertrand, M. P.; Archavlis, A.; Faure, I thank my collaborators, whose names occur in the R. Tetrahedron 1990, 46, 5285.
references below, for their essential contributions to (51) Bertrand, M. P.; Surzur, J.-M.; Oumar-Mahamat, H.; Moustrou, C. J. Org. Chem. 1991, 56, 3089.
the work described. The generous support of the (52) De Riggi, I.; Gastaldi, S.; Surzur, J.-M.; Bertrand, M. P.; Virgili, National Institutes of Health and the National Sci- A. J. Org. Chem. 1992, 57, 6118.
ence Foundation is gratefully acknowledged.
(53) Chuang, C.-P. Synlett 1991, 859.
(54) Chuang, C.-P. Tetrahedron Lett. 1992, 33, 6311.
(55) Chuang, C.-P.; Wang, S.-F. Tetrahedron Lett. 1994, 35, 1283.
XIV. References and Notes
(56) Chuang, C.-P.; Wang, S.-F. Synth. Commun. 1994, 24, 1493.
(57) Chuang, C.-P.; Wang, S.-F. Tetrahedron Lett. 1994, 35, 4365.
(1) (a) Curran, D. P. Synthesis 1988, 417; 489. (b) Jasperse, C. P.;
(58) Citterio, A.; Cerati, A.; Sebastiano, R.; Finzi, C.; Santi, R.
Curran, D. P. Chem Rev. 1991, 91, 1237.
Tetrahedron Lett. 1989, 30, 1289.
(2) Giese, B. Radicals in Organic Synthesis: Formation of Carbon- (59) Citterio, A.; Santi, R.; Fiorani, T.; Strologo, S. J. Org. Chem. Carbon Bonds; Pergamon Press: Oxford, 1986.
1989, 54, 2703.
(60) Citterio, A.; Fancelli, D.; Finzi, C.; Pesce, L.; Santi, R. J. Org. (3) C-Radikale. In Houben-Weyl Methoden der Organischen Chimie; Chem. 1989, 54, 2713.
Regitz, M.; Giese, B., Eds.; Thieme: Stuttgart, 1989; Vol. E 19A.
(61) Citterio, A.; Sebastiano, R.; Nicolini, M.; Santi, R. Synlett. 1990,
(4) Julia, M. Acc. Chem. Res. 1971, 4, 386.
(5) Breslow, R.; Olin, S. S.; Groves, J. T. Tetrahedron Lett. 1968,
(62) Citterio, A.; Pesce, L.; Sebastiano, R.; Santi, R. Synthesis 1990,
(6) Heiba, E. I.; Dessau, R. M.; Koehl, W. J., Jr. J. Am. Chem. Soc. (63) Citterio, A.; Sebastiano, R.; Marion, A.; Santi, R. J. Org. Chem. 1968, 90, 5905.
1991, 56, 5328.
(7) Bush, J. B., Jr.; Finkbeiner, H. J. Am. Chem. Soc. 1968, 90, 5903.
(64) Citterio, A.; Sebastiano, R.; Cavayal, M. C. J. Org. Chem. 1991,
(8) de Klein, W. J. In Organic Synthesis by Oxidation with Metal 56, 5335.
Compounds; Mijs, W. J., de Jonge, C. R. H., Eds.; Plenum (65) Santi, R.; Bergamini, F.; Citterio, A.; Sebastiano, R.; Nicolini, Press: New York, 1986; pp 261 314.
M. J. Org. Chem. 1992, 57, 4250.
(9) Badanyan, Sh. O.; Melikyan, G. G.; Mkrtchyan, D. A. Russ. (66) Citterio, A.; Marion, A.; Maronati, A.; Nicolini, M. Tetrahedron Chem. Rev. 1989, 58, 286; Uspekhi Khimii 1989, 58, 475.
Lett. 1993, 34, 7981.
(10) Melikyan, G. G. Synthesis 1993, 833.
(67) Citterio, A.; Nicolini, M.; Sebastiano, R.; Carvajal, M. C.; (11) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519.
Cardani, S. Gazz. Chim. Ital. 1993, 123, 189.
(12) Heiba, E. I.; Dessau, R. M. J. Org. Chem. 1974, 39, 3456.
(68) Citterio, A.; Sebastiano, R.; Nicolini, M. Tetrahedron 1993, 49,
(13) Corey, E. J.; Kang, M.-C. J. Am. Chem. Soc. l984, 106, 5384.
(14) Snider, B. B.; Mohan, R. M.; Kates, S. A. J. Org. Chem. 1985,
(69) Citterio, A.; Carvajal, M. C.; Mele, A.; Nicolini, M.; Santi, R.; 50, 3659.
Sebastiano, R. J. Chem. Soc., Perkin Trans. 2 1993, 1973.
(15) Ernst, A. B.; Fristad, W. E. Tetrahedron Lett. 1985, 26, 3761.
(70) Bergamini, F.; Citterio, A.; Gatti, N.; Nicolini, M.; Santi, R.; (16) Snider, B. B.; Mohan, R. M.; Kates, S. A. Tetrahedron Lett. 1987,
Sebastiano, R. J. Chem. Res. S 1993, 364.
28, 841.
(71) Cossy, J.; Leblanc, C. Tetrahedron Lett. 1989, 30, 4531.
(17) Mohan, R.; Kates, S. A.; Dombroski, M.; Snider, B. B. Tetrahe- (72) Cossy, J.; Thellend, A. Tetrahedron Lett. 1990, 31, 1427.
dron Lett. 1987, 28, 845.
(73) Cossy, J. Pure Appl Chem. 1992, 64, 1883.
(18) Snider, B. B.; Dombroski, M. A. J. Org. Chem. 1987, 52, 5487.
(74) Cossy, J.; Bouzide, A.; Leblanc, C. SynLett. 1993, 202.
Mn(III)-Based Oxidative Free-Radical Cyclizations Chemical Reviews, 1996, Vol. 96, No. 1 363
(75) Cossy, J.; Bouzide, A. J. Chem. Soc., Chem. Commun. 1993,
(123) Hessel, L. W.; Romers, C. Rec. Trav. Chim. 1969, 88, 545.
(124) Richert, S.; Tsang, P. K. S.; Sawyer, D. T. Inorg. Chem. 1988,
(76) Cossy, J.; Bouzide, A. Tetrahedron Lett. 1993, 34, 5583.
27, 1814; 1989, 28, 2471.
(77) Narasaka, K.; Miyoshi, N.; Iwakura, K.; Okauchi, T. Chem. Lett. (125) Figgis, B. N.; Raston, C. L.; Sharma, R. P.; White, A. H. Aust. 1989, 2169.
J. Chem. 1978, 31, 2545.
(78) Narasaka, K.; Iwakura, K.; Okauchi, T. Chem. Lett. 1991, 423.
(126) Dewar, M. J. S.; Nakaya, T. J. Am. Chem. Soc. 1968, 90, 7134.
(79) Iwasawa, N.; Hayakawa, S.; Isobe, K.; Narasaka, K. Chem. Lett. (127) Dunlap, N. K.; Sabol. M. R.; Watt, D. S. Tetrahedron Lett. 1984,
1991, 1193.
25, 5839.
(80) Iwasawa, N.; Hayakawa, S.; Funahashi, M.; Isobe, K.; Narasaka, (128) Demir, A. S.; Jeganathan, A.; Watt, D. S. J. Org. Chem. 1989,
K. Bull. Chem. Soc. Jpn. 1993, 66, 819.
54, 4020.
(81) Iwasawa, N.; Funahashi, M.; Hayakawa, S.; Narasaka, K. Chem. (129) Demir, A. S.; Sayrac, T.; Watt, D. S. Synthesis 1990, 1119.
Lett. 1993, 545.
(130) Demir, A. S.; Camkertin, N.; Akgun, H.; Tanyeli, C.; Mahasneh, (82) Zoretic, P. A.; Yu, B. C.; Casper, M. L. Synth. Commun. 1989,
A. S.; Watt, D. S. Synth. Commun. 1990, 20, 2279.
19, 1859.
(131) Demir, A. S.; Akgu¨n, H.; Tanyeli, C.; Sayrac, S.; Watt, D. S.
(83) Zoretic, P. A.; Ramchandani, M.; Casper, M. L. Synth. Commun. Synthesis 1991, 719.
1991, 21, 915.
(132) Demir, A. S.; Jeganathan, A. Synthesis 1992, 235.
(84) Zoretic, P. A.; Ramchandani, M.; Casper, M. L. Synth. Commun. (133) Demir, A. S.; Saatcioglu, A. Synth. Commun. 1993, 23, 571.
1991, 21, 923.
(134) Williams, G. J.; Hunter, N. R. Can. J. Chem. 1976, 54, 3830.
(85) Zoretic, P. A.; Weng, X.; Caspar, M. L.; Davis, D. G. Tetrahedron (135) Hirao, T.; Fujui, T.; Ohshiro, Y. J. Organomet. Chem. 1991, 407,
Lett. 1991, 32, 4819.
(86) Zoretic, P. A.; Weng, X.; Biggers, C. K.; Biggers, M. S.; Caspar, (136) Kende, A. S.; Koch, K. Tetrahedron Lett. 1986, 27, 6051.
M. L.; Davis, D. G. Tetrahedron Lett. 1992, 33, 2637.
(137) Kende, A. S.; Ebetino, F. J.; Ohta, T. Tetrahedron Lett. 1985,
(87) Zoretic, P. A.; Shen, Z.; Wang, M.; Riberio, A. A. Tetrahedron 26, 3063.
Lett. 1995, 36, 2925.
(138) Leboff, A.; Carbonnelle, A. C.; Alazard, J. P.; Thal, C.; Kende, (88) Zoretic, P. A.; Zhang, Y.; Riberio, A. A. Tetrahedron Lett. 1995,
A. S. Tetrahedron Lett. 1987, 28, 4163.
36, 2929.
(139) Kende, A. S.; Koch, K.; Smith, C. A. J. Am. Chem. Soc. 1988,
(89) Allegretti, M.; D'Annibale, A.; Trogolo, C. Tetrahedron 1993, 49,
110, 2210.
(140) Iqbal, J.; Kumar, T. K. P.; Manogaran, S. Tetrahedron Lett. 1989,
(90) D'Annibale, A.; Trogolo, C. Tetrahedron Lett. 1994, 35, 2083.
30, 4701.
(91) Bosman, C.; D'Annibale, A.; Resta, S.; Trogolo, C. Tetrahedron (141) Tarakeshwar, P.; Iqbal, J.; Manogaran, S. Tetrahedron 1991,
1994, 50, 13847.
47, 297.
(92) Bremner, J. B.; Jaturonrusmee, W. Aust. J. Chem. 1990, 43,
(142) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Tetrahedron 1991, 47, 6457.
(143) Baciocchi, E.; Paolobelli, A. B.; Ruzziconi, R. Tetrahedron 1992,
(93) Cabri, W.; Candiani, I.; Bedeschi, A. Tetrahedron Lett. 1992, 33,
48, 4617.
(144) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140.
(94) Cabri, W.; Candiani, I.; Bedeschi, A. J. Chem. Soc., Chem. (145) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1985, 26, 4291.
Commun. 1994, 597.
(95) Holzegrabe, U.; Reinhardt, J.; Stoll, E. Arch. Pharm. 1993, 326,
(146) Fujimoto, N.; Nishino, H.; Kurosawa, K. Bull Chem. Soc. Jpn. 1986, 59, 3161.
(96) Artis, D. R.; Cho, I.-S.; Muchowski, J. M. Can. J. Chem. 1992,
(147) Kochi, J. K. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York, 70, 1838.
1973; Vol. 1, Chapter 11.
(97) Ryu, I.; Alper, H. J. Am. Chem. Soc. 1993, 115, 7543.
(148) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351.
(98) Aidhen, I. S.; Narasimhan, N. S. Tetrahedron Lett. 1989, 30,
(149) Jenkins, C. L.; Kochi, J. K. J. Am. Chem. Soc. 1972, 94, 843.
5323; Ind. J. Chem. 1993, 32b, 222.
(150) Vinogradov, M. G.; Dolinko, V. I.; Nikishin, G. I. Bull. Nat. Acad. (99) Paquette, L. A.; Schaefer, A. G.; Springer, J. P. Tetrahedron Sci. USSR. Ser. Chem. 1984, 1884; Izv. Akad. Nauk SSSR., Ser.
1987, 43, 5567.
Khim. 1984, 2065.
(100) Peterson, J. R.; Egler, R. S.; Horsley, D. B.; Winter, T. J.
(151) Vinogradov, M. G.; Dolinko, V. I.; Nikishin, G. I. Bull. Nat. Acad. Tetrhaedron Lett. 1987, 28, 6109.
Sci. USSR. Ser. Chem. 1984, 334; Izv. Akad. Nauk SSSR., Ser.
(101) Rama Rao, A. V.; Rao, B. V.; Reddy, D. R.; Singh, A. K. J. Chem. Khim. 1984, 375.
Soc., Chem. Commun. 1989, 400.
(152) Tagegami, S.; Yamada, T.; Nishino, H.; Korp, J. D.; Kurosawa, (102) Rama Rao, A. V.; Singh, A. K.; Reddy, K. M.; Ravikumar, K. J. K. Tetrahedron Lett. 1990, 31, 6371.
Chem. Soc., Perkin Trans. 1 1993, 3171.
(153) Nishino, H.; Tagegami, S.; Yamada, T.; Korp, J. D.; Kurosawa, (103) Colombo, M. I.; Signorella, S.; Mischne, M. P.; Gonzalez-Sierra, K. Bull. Chem. Soc. Jpn. 1991, 64, 1800.
M.; Ruveda, E. A. Tetrahedron 1990, 46, 4149.
(154) Qian, C.-Y.; Yamada, T.; Nishino, H.; Kurosawa, K. Bull. Chem. (104) Oshima, T.; Sodeoka, M.; Shibaskai, M. Tetrahedron Lett. 1993,
Soc. Jpn. 1992, 65, 1371.
34, 8509.
(155) Qian, C.-Y.; Nishino, H.; Kurosawa, K. Bull. Chem. Soc. Jpn. (105) Warsinsky, R.; Steckhan, E. J. Chem.Soc., Perkin Trans. 1 1994,
1991, 64, 3557.
(156) Yamada, T.; Iwahara, Y.; Nishino, H.; Kurosawa, K. J. Chem. (106) White, J. D.; Somers, T. C.; Yager, K. M. Tetrahedron Lett. 1990,
Soc., Perkin Trans. 1 1993, 609.
31, 59.
(157) Qian, C.-Y.; Nishino, H.; Kurosawa, K. J. Heterocycl. Chem. 1993,
(107) Coleman, J. P.; Hallcher, R. C.; McKackins, D. E.; Rogers, T.
30, 209.
E.; Wagenknecht, J. H. Tetrahedron 1991, 47, 809.
(158) Qian, C.-Y.; Nishino, H.; Kurosawa, K.; Korp, J. D. J. Org. Chem. (108) Shundo, R.; Nishiguchi, I.; Matsubara, Y.; Hirashima, T. Chem. 1993, 58, 4448.
Lett. 1990, 2285.
(159) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24,
(109) Shundo, R.; Nishiguchi, I.; Matsubara, Y.; Toyoshima, M.; Hirashima, T. Chem. Lett. 1991, 185.
(160) Ryu, I.; Ando, M.; Ogawa, A.; Murai, S.; Sonoda, N. J. Am. Chem. (110) Shundo, R.; Nishiguchi, I.; Matsubara, Y.; Hirashima, T. Chem. Soc. 1983, 105, 7192. For related examples see: Murai, S.; Ryu,
Lett. 1991, 235.
I.; Sonoda, N. J. Organometal. Chem. 1983, 250, 121. Ryu, I.;
(111) Shundo, R.; Nishiguchi, I.; Matsubara, Y.; Hirashima, T. Tet- Suzuki, H.; Ogawa, A.; Kambe, N.; Sonoda, N. Tetrahedron Lett. rahedron 1991, 47, 831.
1988, 29, 6137.
(112) Ne´de´lec, J. Y.; Nohair, K. Synlett. 1991, 659.
(161) Ryu, I.; Matsumoto, K.; Kameyama, Y.; Ando, M.; Kusumoto, (113) (a) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 524.
N.; Ogawa, A.; Kambe, N.; Murai, S.; Sonoda, N. J. Am. Chem. (b) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1972, 94, 2888.
Soc. 1993, 115, 12330.
(114) Fristad, W. E.; Peterson, J. R. J. Org. Chem. l985, 50, 10.
(162) Booker-Milburn, K. I. Synlett 1992, 809.
(115) Fristad, W. E.; Hershberger, S. S. J. Org. Chem. 1985, 50, 1026.
(163) Booker-Milburn, K. I.; Thompson, D. F. Synlett 1993, 592.
(116) Fristad, W. E.; Peterson, J. R.; Ernst, A. B. J. Org. Chem. 1985,
(164) Burnell, R. H.; Girard, M. Synth. Commun. 1990, 20, 2469.
50, 3143.
(165) Burnell, R. H.; Coˆte, C.; Girard, M. J. Nat. Prod. 1993, 56, 461.
(117) Fristad, W. E.; Peterson, J. R.; Ernst, A. B.; Urbi, G. B.
(166) Shishido, K.; Goto, K.; Tsuda, A.; Takaishi, Y.; Shibuya, M. J. Tetrahedron 1986, 42, 3429.
Chem. Soc., Chem. Commun. 1993, 793.
(118) Yang, F. Z.; Trost, M. K.; Fristad, W. E. Tetrahedron Lett. 1987,
(167) Liu, Z.; Xu, F. Tetrahedron Lett. 1989, 30, 3457.
28, 1493.
(168) Iwasawa, N.; Funahashi, M.; Narasaka, K. Chem. Lett. 1994,
(119) Baciocchi, E.; Giese, B.; Farshchi, H.; Ruzziconi, R. J. Org. Chem. 1990, 55, 5688.
(169) Takemoto, Y.; Ohra, T.; Koike, H.; Furuse, S.-I.; Iwata, C.; (120) Diversi, P.; Forte, C.; Franceschi, M.; Ingrosso, G.; Lucherini, Ohishi, H. J. Org. Chem. 1994, 59, 4727.
A.; Petri, M.; Pinzino, C. J. Chem. Soc., Chem. Commun. 1992,
(170) Dale, J.; Morgenlie, S. Acta Chem. Scand. 1970, 24, 2408.
(171) Breuilles, P.; Uguen, D. Bull. Chim. Soc. Fr. 1988, 705.
(121) Kern, J. M.; Federlin, P. Tetrahedron Lett. 1977, 837.
(122) Kern, J. M.; Federlin, P. Tetrahedron 1978, 34, 661.
364 Chemical Reviews, 1996, Vol. 96, No. 1


THE EPIDEMIOLOGY OF TETRACYCLINE AND CEFTIOFUR RESISTANCE IN COMMENSAL ESCHERICHIA COLI MATTHEW THOMAS MCGOWAN B.S., Kansas State University, 2011 submitted in partial fulfillment of the requirements for the degree MASTER OF SCIENCE Department of Biomedical Science College of Veterinary Medicine KANSAS STATE UNIVERSITY Manhattan, Kansas Dr. H. Morgan Scott

Neuroglia in neurodegeneration

Neuroglia in neurodegeneration Michael T. Henekaa,⁎, José J. Rodríguezb,e, Alexei Verkhratskyc,d,e,⁎ aKlinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, Sigmund-Freud-Str. 25, 53127 Bonn, GermanybIKERBASQUE, Basque Foundation for Science, 48011, Bilbao, SpaincDepartment of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, SpaindFaculty of Life Sciences, The University of Manchester, Manchester, UKeInstitute of Experimental Medicine, ASCR, Prague, Czech Republic