Aldehydes and ketones PATRICK G. STEEL Department of Chemist% Science Laboratories, South Road, Durham DHl3LE, UK Reviewing the literature published between October 1994 and September 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995,2, 151 1 1.1 1.2 1.3 2 3 4 5 5.1 5.2 5.3 6 6.1 6.2 7 Synthesis of saturated aldehydes and ketones Redox methods Umpolung methods General methods Synthesis of aromatic aldehydes and ketones Synthesis of cyclic ketones Protection and deprotection strategies Synthesis of functionalised aldehydes and ketones Unsaturated aldehydes and ketones a-Heteroatom substituted aldehydes and ketones Dicarbonyl compounds Reactions of aldehydes and ketones The aldol reaction and other enolate additions Conjugate addition reactions References 1 Synthesis of saturated aldehydes and ketones 1.1 Redox methods The Oppenauer oxidation forms a classical method for the conversion of alcohols to carbonyl compounds.Recent developments in the general area of Oppenauer-Meerwein-Ponndorf-Verley redox processes have been reviewed.' Oppenauer type oxidations can also be achieved through the mediation of zirconocene derived catalysts although this latter route does require the use of one equivalent of a sacrificial aldehyde.2 Chromium reagents retain a predominant role in this oxidation, although there is still demand for more convenient procedures. In this respect, the use of polychromates have been advocated as the reagents of ~hoice.~ These not only provide equivalent yields and selectivities, as do PCC and PDC, but are much cheaper.Similarly 18-crown-6 complexes of various chromate salts have been developed as more soluble, non-hygroscopic alternatives to PCC4 Other enhancements in this area have focused on the use of sub-stoichiometric quantities of chromium salts in the presence of co-oxidants such as sodium per~arbonate.'~~ In the second of these reports it has been found that the use of phase transfer catalysis provides enhanced efficiency although simple primary aliphatic alcohols are prone to over-oxidation. This proviso also applies to many of the reported alternatives to chromium catalysts which have included complexes based on palladium,' cobalt,' rhenium' and ruthenium." However, ruthenium porphyrin catalysts are suitable for the lo2 mediated oxidation of the complete spectrum of alcohols.'' C-H bond activation can be competitive with such ruthenium catalysts and this aspect has been exploited in the direct synthesis of carbonyl compounds from hydrocarbons.The use of peracids as the co-oxidant has been shown to provide much better conversions and ketone: alcohol selectivity than the previously favoured TBHP.12 Similar transformations, albeit with lower efficiencies, have been reported for a variety of other systems13 and in general, at present, the transformation is only synthetically viable for benzylic methylene ~ n i t s . ' ~ carbonyl groups - the Wacker reaction - have been reported. In particular, the use of j-cyclodextrins has been advocated for the oxidation of higher a-olefins. Whilst, as phase transfer catalysis, there is some precedent for this observation, this latest report utilises partially methylated cyclodextrins to provide optimal yields, rates and sele~tivities.'~ Interestingly, it has been shown that the regio- chemistry of the Wacker oxidation can be controlled by simple variations in substrate structure (Scheme 1).l6 today is the Dess-Martin periodinane.Recent reports have suggested that the addition of a stoichiometric amount of water can provide a more Modifications to the direct oxidation of alkenes to Amongst the more popular oxidants employed 90% ?\ 9\ Scheme 1 Steel: Aldehydes and ketones 15 1effective oxidant.17 The authors’ comment on the effect of prevailing humidity illustrate the difficulties that can arise. In this respect it has been noted that the use of o-iodoxybenzoic acid, which is the precursor to the Dess-Martin reagent, is not only an effective and selective oxidant but is less sensitive to moisture. The only drawback to this reagent is the requirement for DMSO as the solvent.18 in the conversion of sec-alkyl ethers into the corresponding ketones in good yield.Similar transformations have previously been reported with dimethyl dioxirane although this new modification appears more facile.” The latter reagent has been advocated as the reagent of choice for the selective oxidation of the secondary alcohol of cyclic and a- and p-linear diols. For saturated linear diols hydrogen peroxide in the presence of TS-1 zeolite proves more effective.20 This combina- tion is also effective for the oxidation of secondary benzylic amines although oxime formation is competitive.21 Oximes may be converted to the corresponding carbonyl compound on treatment with manganese dioxide; under these mild conditions a,P-unsaturated carbonyl groups do not suffer from olefin isomerisation.22 Similar conversions are also possible using copper nitrate or silver carbonate supported on silica or bentonite clay respectively” (see also Section 4).Enamines undergo oxidative cleavage to the homologous ketone upon treatment with a variety of reagents. A systematic survey on the use of potassium dichromate has shown that a biphasic solvent mixture can help inhibit over-oxidation which is a problem for substrates lacking P-sub~tituents.~~ Approaches that minimise side products are of interest and in this respect the electrochemically mediated oxidation of primary and secondary alcohols has been reported.25 In general these procedures appear to be more effective with benzylic alcohol substrates.26 In a similar vein, Pirrung has reported that the photolysis of substituted benzoylformate esters affords the corresponding ketones in good yield.27 The relatively long wavelength employed means that most common chromophores are unaffected by this transformation.Minimisation of the problems associated with heavy metal oxidants can also be achieved through the use of supported reagents: reviews on the use of silicates28 and ~ i r c o n i a ~ ~ have appeared. Enzymatic oxidation is also another possibility which can result in a kinetic resolution of suitably structured alcohols.30 Procedures €or the efficient, mild oxidative cleavage of 5-substituted furfurals to y-ketoester~~~ and nitroalkenes to the corresponding ketone32 have been published. Selective reduction of acid chlorides has been recognised as an efficient method for aldehyde synthesis.Excellent yields are obtained in the zinc- copper couple mediated reduction of an in situ generated acyl phosphonium salt .” Transfer hydrogenation remains a favourite method for the conjugate reduction of enones. Aqueous phase Perfluoroalkyl oxaziridines have been employed reductions are possible using the water soluble complex, Rh[(ptah)(pta)2Cl]C1 {where pta is 1,3,5 tria~a-7-phosphaadamantane}.~ Further reports have appeared on the use of the ammonium formate/Pd-C system which may be employed in the presence of both non-conjugated olefins and carbonyl group^.'^ Similar claims have been made for the use of sodium dithionate in water-dioxane solvent systems.Contrary to previous reports it is suggested that the use of phase transfer catalysis is detriment a1 to the c hemoselect ivity. 36 1.2 Umpolung methods Nucleophilic acyl radicals can be considered as umpolung reagents and this area remains one of some considerable activity. Aryl ~elenides~~ and chromium carbene cornplexe~’~ are both suitable precursors. The latter combine with most electrophilic acceptor olefins although efficient yields are only obtained with aromatic carbene complexes which lack ortho substituents. Electro- chemical reduction of an acyl chloride provides an alternative entry point and the resultant radical combines with carbon dioxide to produce a-keto- acids in moderate yield^.'^ Similar products can be more efficiently accessed through the use of lithiated ethoxyacetylene.Treatment of the initial adduct with neutral KMn04 affords the P-hydroxy a-keto ester. If aldehydes are used as the sub- strate this can provide a very rapid access to 1,2,3- tricarbonyl species.40 Collman’s reagent, Na2[Fe(C0)4], provides a number of routes to ketones. However, it is an extremely pyrophoric compound and this has restricted its use. The corresponding potassium salt, introduced by Yamashita, is much more stable and a simplified preparation has recently been published.41 co-workers have illustrated the use of protected 1,1,l-trifluoroethanol as a precursor to a variety of a, a-difluoro ketones (Scheme 2).42 a-Pefluoroalkyl aldehydes can be accessed from the treatment of perfluoroalkyl ketones with trimethylsilylthia~ole.~’ This represents the first reported addition of this In an elegant series of papers, Percy and r ODECI OH i.NaH, THF, 0 “C jDEc 2 eq. LDA l ~ f ~ ~ 1 THF, -78 “C, 20 rnin F3CJ ii.Et2NCOCI * F3C I i. ECHO ii. NH&I (aq.) F2CH Et ODEC 68% Scheme 2 152 Contemporary Organic Synthesisumpolung reagent to ketones and reflects the increased reactivity due to the perfluoroalkyl group. P-Chlorovinyl acetals undergo facile lithium- halogen exchange and as such represent a P-acyl vinyl anion eq~ivalent.~~ The generation of a-alkoxyvinyllithium is enhanced if tetrahydropyran is used as the solvent since this avoids contamination with acetaldehyde enolate which can be a problem in THF.45 Similarly 8-thio ketals can function as bis-homoenolate equivalent^.^^ Finally, cyanophosphonates may be employed as asymmetric cyanohydrin equivalents, undergoing alkylation with high diastereo~electivity.~~ 1.3 General methods Predominant in the modern repertoire for the preparation of ketones (and aldehydes) from a carboxylate function is the Weinreb amide, RC(=O)N(OMe)Me, and these can be efficiently prepared from the free acid using bromomethyl pyridinium iodide as a relatively inexpensive coupling agent."' Alternatively, esters may be directly converted to the corresponding ketone through consecutive treatment with the amine hydrochloride followed by 2 equiv.of the appropriate ~rganometallic.~~ The amide is sufficiently stable to be compatible with a number of other synthetic transformations. For example, the asymmetric aldol reaction of N-methoxy-N-methyl- cr-isocyanoacetamide 1 affords the corresponding oxazoline 2 which may subsequently be combined with a range of organometallic reagents to provide access to both amino and hydroxy substituted ketones and aldehydes (Scheme 3).50 1 2 t NHP R'q* P o 0 Scheme 3 A number of alternative leaving groups have been developed including piperidino carbamates which couple with the complete gamut of unhindered organolithiums to provide symmetrical ketones in excellent yield." Unsymmetrical ketones are accessible through the use of acyl-l,2-diazole~~~ or imidazole based hydra~ines.~~ The former also react with Reformatsky reagents to afford b-keto esters in moderate to good yield, whilst the latter, on reduction with DIBALH, provide aldehydes in excellent yield.Although acyl chlorides are normally too reactive to be used in this context it has been reported that in situ generated lithium tetra- alkylgallates do not add to ketones and can be employed in this respect. However, the difference in the migratory aptitude of the gallate substituents [Br > Ph > PhC = C > primary alkyl >secondary alkyl] is not always large and mixtures of products can result. In general, alkynyl transfer can be more effectively achieved using thallium reagents.54 sonochemical Barbier reaction have been p~blished.~' Trifluoromethyl ketones can be obtained through the in situ lithium-halogen exchange reaction between alkyl iodides and one equivalent of tert-butyllithium in the presence of a fluoroacyl cation eq~ivalent.~~ The stoichiometry of this process is crucial for good yields to be obtained.The same products are produced in the reaction of acid chlorides with trifluoroacetic anhydride.57 A similar synthesis of aliphatic P-keto esters can be achieved from the half ester of malonic Alternatively, a-bromo esters undergo a Claisen type condensation with concomitant reduction of the C-Br bond on treatment with samarium iodide (see also Section 6.1).59 These and other syntheses of P-keto esters have been reviewed.60 A trifluoromethoxy group is essential in the free radical mediated synthesis of a-keto esters from a-alkoxyacrylates." a-Epoxy esters undergo low temperature addition of organometallics to afford the corresponding ketone in good yield.h2 The presence of trimethylsilyl chloride is beneficial and becomes essential if Grignard reagents are used.2-Tetrahydrofuranyl carboxylate is converted to the corresponding ketone on reaction with 2 equiv. of an organometallic nucleophile; the various options for this particular conversion have been s~rveyed.~' The resultant tetrahydrofuranyl ketones are readily cleaved to the corresponding cu-hydroxy ketone on reaction with Sm12. This transformation proceeds via the samarium enolate which may be efficiently trapped with a range of electrophile~.~~ Homologous p-tetrahydrofuryl ketones can be accessed through a palladium mediated tandem radical cyclisation- carbonylation of alkyl 9-BBN derivatives. This report confirms the radical mediated nature of this previously reported route to acyclic ketones.65 P-Keto amides are produced in the lanthanide mediated coupling of azaketones and aldehydes.66 The intermediate cr-imino-oxetanes can also be used to produce P-lactams.A P-keto acylsilane is produced in the unusual aldol coupling of an acylsilane with excess benzaldehyde. However, the yield is only moderate and the generality was not stated.67 On treatment with lead tetraacetate and carbon monoxide, tertiary cyclobutanols undergo ring opening acylation to afford substituted 8-keto esters in moderate yields.68 Isomeric oxetanes undergo rhodium mediated carbonylative ring opening to produce the 8-silyloxy aldehyde.69 Unlike earlier Full details on the scope and limitations of the Steel: Aldehydes and ketones 153reports, this modification only requires stoichiometric quantities of the starting oxetane.Epoxides undergo rearrangement to carbonyl compounds on treatment with Lewis acids; there have been a number of reports in this area focusing on the aldehyde : ketone selectivity ~btainable.~' With styrene oxides, the use of strong Lewis acids may be avoided through the simple use of silica gel.71 Very high chemoselectivity is obtained via the utilisation of different phosphine ligands in the palladium acetate mediated version of this reaction (Scheme 4).72 A Pd(OAC)z, PPh3 PhH, reflux Scheme 4 Palladium catalysis is also effective in promoting the Claisen rearrangement and this can produce different stereochemical outcomes to that observed in the thermal modification (Scheme 5).73 In the presence of rhodium salts the Cope rearrangement can also be catalysed although under these conditions the product aldehyde is prone to undergo an intramolecular hydr~acylation.~~ PdCI,(PhCN)2, PhMe, rt, 0.5 h 55% 90 : 10 PhMe, 100 O C , 10 h 57% 11 : 89 Scheme 5 In the presence of TiC14, allylsilanes add to a-diketone ketals to afford a variety of ketonic products via simple acetal substitution followed by pinacol type rearrangement^.^^ Treatment of MEM ethers of 6-hydroxy-(E)-vinylsilanes with the same Lewis acid results in C - C bond cleavage and the production of ketones.76 The corresponding (2)- vinylsilane leads preferentially to dihydropyran products.Reactions of alkenyl sulfides 3 also occur with C-C bond cleavage and the Lewis acid mediated reactions of this nucleophile have been extended to include conjugate addition, which proceeds with excellent stereo~electivity.~~ Full details have appeared on the triaZky2- aluminium promoted homologation of aldehydes and ketones with diaz~alkanes,~' the aluminium ?TES SMe 3 trichloride induced rearrangement of aryl tert butyl ketones79 and the palladium mediated addition of alcohols to chiral methacrylates to afford a-chiral aldehydes masked as the corresponding acetal." Aldehydes and ketones masked as the enol ether are accessed through the coupling of an a-methoxy sulfone with a second lithiated sulfone.81 Mixed acetals are produced from the reaction of alcoholic solutions of allylic ethers with CO in the presence of dicobalt octacarbonyl.82 The free aldehyde is the product when water is used as the solvent.Alkynols are converted to ketones in a tandem hydrosilylation-isomerisation process catalysed by cationic rhodium(1) c~mplexes.~' Although the reaction can be carried out in a single pot the yields are better if each step is achieved separately. appear with a particular focus on the stereo- selectivity of the process.&4 Reports on the regioselectivity of diene~,'~ acrylateS6 and vinyl heterocycless7 have been published. However, the main body of work in this area has been concerned with control of the absolute stereochemistry and in this respect a number of new chiral ligands have been identified." Labile aldehydes can be masked as the acetal in situ through the use of triethyl orthoformate; further developments in this strategy allow this to be achieved at lower pressures and higher rates than had previously been rep~rted.'~ Other enhancements to the efficiency of the hydroformylation process have included hetero- genisation or biphasic/supported aqueous phase media." Developments in hydroformylation continue to 2 Synthesis of aromatic aldehydes and ketones Aryl carbonyl compounds can be accessed through benzylic hydrocarbon oxidation; a number of procedures in this area have been ~ublished.~' Whilst many of these suffer from competitive over- oxidation this is not the case for the enzymatic process utilising l a ~ c a s e .~ ~ In an interesting variant, trichloromethyl aryl groups can be converted to the corresponding aldehyde on reaction with pyridine; a mechanism for this transformation has been proposed.93 Oxidation of the corresponding benzyl alcohol is facile and new protocols and reagents for this conversion have been reported." Calcium borohydride-cyclooctadiene affords a reagent for the efficient reduction of aryl and other non-enolisable esters to the corresponding aldehyde?' popular options for the synthesis of aryl carbonyl Friedel-Crafts methods remain one of the most 154 Contemporay Organic Synthesisunits. Whereas most arenes undergo alkylation with lactones, N-methylpyrrole affords the acylated product in good yield.96 The regiochemistry of substitution of N-sulfonyl pyrroles can be controlled by the nature of the reaction solvent.97 For example, nitromethane favours a strongly dissociated acylium ion which leads to exclusive 3-substitution.Simple acylation can be achieved under very mild conditions using a combination of anhydride, dimethyl sulfide and boron trifluoride." This combination is equivalent in reactivity to acetyl triflate but is much cheaper and simpler in operation. Reports on the efficacy of a number of alternative Lewis acids have been published including rhenium pentacarbonyl bromide,99 hafnium triflate'"" and lanthanide salts of superacids."' The latter are claimed to be even more effective than the previously reported triflates.'02 reaction, scandium triflate is also an effective catalyst for the Fries rearrangement.lo3 This transformation can also be initiated photo- chemically; although this produces isomeric mixtures the product ratios can be enhanced through the appropriate choice of solvent.lW Similar problems befall the synthesis of o-hydroxyphenyl acetones via the Carroll rearrangement of aryl acetoacetates derived from the reaction of p-quinols and diketene.'05 be obtained through the generation of an aryl organometallic reagent which also overcomes problem or regiocontrol.Direct generation of halo aryl copper species is possible from haloiodoarenes and activated copper.lo6 Similar iodoarenes can be converted to the corresponding trifluoromethyl ketone via conversion to the aryl~tannane."~ This latter transformation is catalysed by palladium complexes and a variety of carbonylation processes are similarly promoted.1os A general review of the synthesis of diary1 ketones by such a strategy has been published.1o9 In related processes triaryl- bismuth may be employed as the arene source in a rhodium(1) catalysed coupling reaction,"' whilst iron pentacarbonyl can be used in an aqueous phase version of this synthesis.'" Directed metallation of the arene provides an alternative option for regio- control.'12 Such a process may then be combined with a transition metal catalysed acylation ~equence."~ In an interesting variant on this strategy activation of the ortho hydrogen of an aromatic ketone is possible on treatment with the ruthenium dihydro complex [Rh(H),CO(PPh,),], and a full account of this work has been p~blished."~ Benzyne combines with ketene silylacetals with high selectivity to provide access to benzocyclo- butanones with the regiochemistry controlled by the nature of the aryne ~ubstituents."~ The Lewis acid promoted rearrangement of 3-aryl-P-sultams provides aryl ketones or substituted arylethanals in good overall yield.'l6 Aryl methyl ketones are obtained through the reaction of Fischer carbene In addition to promoting the Friedel-Crafts Enhanced reactivity with acylating agents can complexes with chloromethyllithium.'17 Finally, two unusual transformations which produce aryl carbonyl units have appeared. Flash vacuum pyrolysis of 1 ,Zdialkoxybenzene affords mixtures of o-hydroxybenzaldehyde1l8 whilst treatment of a,P-epoxy ketones with the Vilsmeier reagent leads to moderate yields of 2,3-di~hlorobenzaldehydes.'~~ 3 Synthesis of cyclic ketones Cyclopropanone ketals are routinely accessed from ethyl P-halopropionate by treatment with sodium metal and trimethylchlorosilane.However, these conditions can cause difficulties with more complex substrates and the use of highly activated zinc has been advocated.'20 The ring strain associated with cyclopropanes also aids the oxidation of bicyclo [3.1 .O] hexanols to the corresponding 3-bromomethyl ketone.12' Fully protected glycols may be oxidised to 2,3-dihydropyranones by hypervalent iodine reagents.'" The same class of products are also accessible through the asymmetric heteroatom Diels-Alder rea~ti0n.I~~ Oxidation of allylic, benzylic or cyclic alcohols can be achieved by conversion to the diazoacetate followed by rhodium mediated diazoalkane decomp~sition.'~~ Although the yields are only moderate this represents the first reported examples of this particular pathway.The normal pathway for transition metal catalysed decomposition of diazocarbonyl compounds is via C-H insertion and this has been exploited in a number of cyclic ketone syntheses.l3 Cyclic a-diazo P-diketones undergo a photochemically induced ring contraction to the corresponding a-amido cyclic ketone.126 Full details have appeared on the thermolysis of bis(diazo- methyl ketones) to afford cyclic en one^.'^^ Both five- and six-membered rings can be generated with, notably, trans-hydroindenones being accessible in excellent yield, albeit with the proviso that non- symmetrical substrates produce isomeric mixtures.Owing to difficulties in the preparation of the corresponding bis(diazomethylketones), synthesis of cis-hydroindenones is limited in efficiency. However, these are routinely accessible by classical methods and consequently this represents a complementary study. The synthesis of cyclopentenones is dominated by the Pauson-Khand reaction and variants thereof.12' Developments have included the extension to different substrates including a11ene,129 electron deficient alkenes13' and terminal alkyne~.'~' The latter also appear in a catalytic rhodium mediated cyclisation of diyne~."~ Alkynes combine with /?-amino Fischer chromium carbene complexes to form enaminocy~lopentenones.~~~ Different isomeric products are obtained depending on the solvent used.Whereas the vinylcyclopropane-cyclopentene rearrangement proceeds with loss of stereochemical integrity, the corresponding rearrangement of cyclopropylchromium carbene complexes occur with retention of c~nfiguration.'~~ Steel: Aldehydes and ketones 155Cyclopropyl intermediates are also involved in the condensation of y-methoxy vinyl sulfones with a second vinyl sulfone to afford, after hydrolysis, P-cyclopentyl dienones (Scheme 6).i35 This is a further modification of previously reported methodology for the synthesis of P-alkylated cyclic en one^.'^^ Developments to this strategy have now extended this approach to the synthesis of cyclo- pentenone derivatives which previously underwent preferential self ~0ndensation.l~~ Sulfone stabilised anions are also employed in the annulation of a cyclopentanone ring to a pre-existing cyclic a-sulfonium e n ~ n e .' ~ ~ i. Bu'U SOpPh MeO' 1. 5% HCI, THF ii. DBU, MeCN, refiux I n $2" U - 95% Scheme 6 Nazarov cyclisations frequently produce complex mixtures of isomeric cyclopentenones. However, substrates containing a difluoromethylene unit react rapidly at room temperature to afford a single isomer in excellent yield, and this result is attributed to the p-cation destabilising effect of fluorine. However, for optimal yields the use of highly solvating 1,1,1,3,3,3-hexafluoropropanol is required as a co~olvent.'~~ 2,4-Diene- 1,6-diones undergo intramolecular Michael reactions to afford cyclopentenones in moderate yields although the substituent requirements for this pathway are high.140 The nature of the substitution pattern in 1,4-diketones can markedly effect the chemo- selectivity of the aldol cyclisation (Scheme 7).14' The basic nature of many of these cyclisations frequently results in isomerisation of the olefin. This can be avoided in a 'Robinson type annulation' of cyclo- pentenones through a strategy involving alkylation with (Z)-3-bromo-l-i0dopropene.'~~ One pot, five step (imine-enamine tautomerisa- tion, alkylation, aza-Cope rearrangement, Mannich cyclisation, elimination) strategy has been developed for the synthesis of cyclopentenones from aldehydes (Scheme 8). However, in the single example given the level of diastereoselection obtained at the newly formed chiral centre was 1 MeCNp800C rearrangement Mannich readion 1 J 40% overall Scheme 8 A number of Wittig based strategies have been developed for the synthesis of cycl~pentenones.~~~ Notably, stabilised Wittig reagents (e.g.Ph3P=CHC02But) couple with vinyl vicinal tricarbonyl units to produce a cyclic enone in good yield. In a similar fashion a variety of stabilised carbon nucleophiles react to produce cyclo- ~entanedi0nes.l~~ Such stabilised Wittig reagents i. Mg(OMe), MeOH ii. NaOH (aq.) 0 9 1 0 + 9 1 i. Mg(OMe)z, MeoH ii. NaOH (aq.) Me0& 0 7% Scheme 7 156 Contemporary Organic Synthesiscombine with cyclopropanones in a general ring expansion sequence to substituted cyclobutanones from cyclobuta-l,3-diones'48 whilst an efficient ultrasound promoted route to the 1,2-dione has been published.149 Ring expansion of cyclobutanones to cyclopentanones is simply and efficiently achieved upon treatment with samarium iodide-diiodo- methane, although mixtures of regioisomers occur with non-symmetrical Reaction of carbenoids with an alkyne affords 2-ynones in addition to the expected cyclopropenone. A recent report has developed this observation into a general method for the ring expansion of cyclic alkynes to the homologous 2-yn0nes.l~~ A large number of other reports have appeared, detailing ring expansion routes to cyclic ketones promoted by - amongst - Lewis oxidising agents'', and free radical initiator^."^ However, many of these involve multiple steps and/or are substrate specific, and although efficient, the overall yields are only moderate.Medium to large ring-fused tricyclic ketones can be prepared by a sequential Type 2 intramolecular Diels-Alder cycloaddition - ozonolysis - aldol condensation strategy.156 Polycyclic ketones are obtained with excellent control via tandem Diels- Alder rea~ti0ns.l~~ Similar products have also been prepared through a tandem radical cyclisation- Diels-Alder cycloaddition approach. Seven-membered ring ketones are approachable through the TiC1,-promoted intramolecular [4 + 31 cycloaddition reaction of oxyallyl cations. Harmata has examined the diastereoselectivity of this process.158 Oxyallyl cations also combine with olefins in a [3 + 21 cycloaddition to produce cyclo- pentenones. In contrast to most earlier reports, an excess of the olefin trap is not required when bis- sulfenyl ketones are used as the oxyallyl cation precursor.1s9 [6 + 21 Cycloadditions of chromium cycloheptatriene complexes with heterocumulenes are precedented.16' A recent report has demonstrated that chromium carbenes are also suitable 2n components in this process although the present yields are low.The development of efficient asymmetric ketene equivalents continues. The dithiolane dioxide 4 proves to be both accessible and selective.16' An alternative strategy is to use a chiral vinyl sulfate in an intramolecular cycloaddition.'62 +A -O - - "Y" ' O- 4 Bicyclic ketones have also been accessed from substituted cyclic ketones with the crucial bond formation achieved either by anionic16' or free radical cy~lisation.'~~ The latter, mediated by Mn(OAc)3, provides a method for free radical alkylation with alkenes, albeit one limited to products which cannot undergo enolisation.Bridgehead functionalisation of bicyclic ketones is normally difficult and Eaton has introduced the 1,2,4-trihydroxycyclopentane ketal as a controlling group for this operation (Scheme 9).165 I Scheme 9 PhI(0Ac)p d C " 0 & 87% Free radical cyclisation of 6-bromo-6-stannylacyl- silanes provides moderate to excellent yields of the cyclopentanone derived silyl enol ether via a Brook type rearrangement of an a-silyloxyl The anionic Brook rearrangement forms an integral part of the condensation of p-silyl a,P-unsaturated acylsilanes with the conjugated dienolate 5 (Scheme 10). 167 TBS 0 TBSO b \ --Ps 84% Scheme 10 Cyclohexanes are classically prepared by the Dieckman cyclisation.This can theoretically proceed to give two products. Control of the regiochemistry is possible through either base or Lewis acid Steel: Aldehydes and ketones 157bopB 74% 7096 scheme11 promotion (Scheme 11).'68 Attempts to achieve chemoselectivity through the use of Weinreb amides is not always successful with the product ratio depending on the precise conditions employed.'69 Although not intended, the Dieckman cyclisation of chiral bis-oxazolidinones can proceed with high diastereoselectivity and this can provide an efficient entry to enantiopure cyclohexan~nes.~~~ In a homologation of earlier reports cyclo- hexenones are prepared through the copper- catalysed addition of wester functionalised organozinc reagents to yn~ates.'~' Similar products are obtained in good yield from the ruthenium catalysed condensation of 2 equiv.of a P-ketoester with an allylic alcohol or amine.172 Finally, intramolecular umpolung strategies have been employed in the synthesis of cyclic ketones. Electrolytic reduction of a, co-ketoacids in the presence of tributylphosphine affords the corre- sponding a-hydroxycyclic ketone in moderate ~ie1ds.l~~ The reaction is believed to proceed via reduction of an acyl phosphonium salt. Treatment of the cyanohydrin 6 with KHMDS leads after hydrolytic workup to the keto lactol7 (Scheme 12), and this represents the first example of the reaction of a cyanohydrin anion with a lactone ele~trophile.'~~ TBSOyCN i. KHMDS, THF, -78 "C ii. TBAF, rt Ui.NaOH (aq.), E t g , rt HO 6 7 61% Scheme 12 4 Protection and deprotection strategies In the search for milder conditions for protection and deprotection, the use of diallyl acetals has been advocated. Selective deprotection is promoted by rhodium(1) catalysis whilst formation is routinely achieved following the Noyori protoc01.'~~ A modified version of this process has been developed for the mild introduction of the dioxolane a~eta1.l~' a, @-Unsaturated aldehydes are efficiently protected as the dioxolane in the presence of MgS04.177 A significant rate enhancement is observed in the formation of all dioxolanes through the use of microwave irradiati~n'~~ whilst substrate selectivity is obtained in the presence of mont- morillonite clays.'79 Methods for the selective protection of either component of cc-keto aldehydes have been published.18' Geminal diacetates have been advocated as acid-stable, base-labile protecting groups; their efficient synthesis can be achieved in the presence of a fl-zeolite.'81 Acetals may be converted to mixed acetals on treatment with appropriate nucleophiles (eg.thiols, etc.) in the presence of a dicyano ketene acetal as a novel n acid catalyst.182 Oxathiolanes can similarly be prepared through the use of TMSOTf or bismuth(rI1) salts as strong ~ata1ysts.l~~ These also promote the formation of dithioacetals. Selectivity in the preparation of the latter is observed through the use of catalytic amounts of CAN (ceric ammonium nitrate) as the promoter. Aldehydes react with ketones and cyclic ketones in preference to acyclic and aromatic ketones.'84 Selenium dioxide has been suggested as an efficient reagent for the deprotection of dithioacetals.However, an excess is required and the use of acetic acid as the solvent is e~sentia1.l~~ Oxathiolanes are much more labile and these can readily be exchanged with a polymer bound nitrobenzaldehyde residue. The same reagent is also effective for the conversion of thioketones to ketones."' Molybdenyl(v1) acetylacetonate proves to be a mild and efficient catalyst for the deprotection of a range of acetals and ketal~.'*~ The latter are efficiently cleaved by NO2 but acetals undergo oxidation to a-hydroxy esters.'88 a-Chloro acetals are converted to the corresponding a-chloro aldehyde upon treatment with a combination of acetic anhydride and acetyl chloride.Although a-bromo acetals are substrates, halogen exchange also occurs.189 Enol ethers represent an alternative mode of protection; an efficient mild synthesis of this functionality from chiral alcohols has been reported.'" Protection/deprotection strategies reduce synthetic efficiency; methodology which avoids this has been reported. Commins has previously reported that aldehydes could be masked in situ through the formation of amide base adducts. Higher stabilities in this process can be obtained through the use of Weinreb amide.'" In a similar vein Yamamoto has extended his work on the protection of carbonyl groups through the use of bulky aluminium Lewis acids. In these latest reports the promotion of 1,4 (conjugate) addition to enones in preference to 1,2-addition at alkyllithium reagents is 0ut1ined.l~~ 5 Synthesis of functionalised aldehydes and ketones 5.1 Unsaturated aldehydes and ketones Oxidation of enol silanes (silyl enol ethers) to the corresponding enone using stoichiometric palladium 158 Contemporary Organic Synthesisreagents is well established.Larock has developed a procedure in which this conversion can be achieved using catalytic quantities of the palladium Alternatively, this conversion can be efficiently realised using CAN in DMF.'94 Electrochemical oxidation of the corresponding enol acetate also provides the enone. However, this process is only efficient if a B-trimethylsilyl group is present.'" More traditionally, unsaturation is introduced in a two step procedure involving activation and elimination.This can be achieved in a one pot process using potassium enolates and methoxy- phenyl sulfoxide as the ele~trophile.'~~ Similarly the nitro group can function as the leaving group; this forms part of a multistep elongation of aldehydes to enedi~nes.'~~ Similar products can be obtained from the photochemical addition of 302 to fur an^.'^^ In this latter case the olefin is exclusively of cis geometry. Steroidal enediones are accessed through the PCC oxidation of the corresponding allylic alcohol." a, /3-Unsaturated aldehydes are formed on treatment of isoxazolines with methyl iodide. The yields are only moderate unless a second oxidation step follows.2oo Oxidative cyclisation of anisole containing oximes promoted by Bu4NRe04 affords good yields of spirocyclic dienones.201 Similar products are also obtained in the radical cyclisation of a functionalised quinol.202 Linear dienones are formed in the palladium catalysed rearrangement of 2-acyl- 3-vinyl a~iridines.~'~ Aliphatic Friedel-Crafts type acylations have been explored as routes to unsaturated ketones using acyl fluoroborate salts or electrolytic reduction of acid chlorides to provide the ele~trophile.~'~ Lewis acid catalysed addition of acid chlorides to enynes affords mixtures resulting from both 1,2- and 1,4-addition, with the allenyl ketone predominating as the degree of substitution of the enyne increase^.^'^ Alkynes also couple directly with aldehydes or ketones in the presence of tin halide- tertiary amine catalyst mixtures.Good EIZ selectivity is obtained whilst the use of trimethylsilyl chloride with ketone substrates affords the P, y-unsaturated product.206 Other P, y-unsaturated ketones are available through the condensation of dienylmagnesium complexes with esters and lac tone^,^'^ the trimethylsilyl chloride promoted deconjugation of P-bromo or P-iodo enones,208 or the palladium mediated carbonylative coupling of organozinc reagents with various alkylating agents.209 ruthenium catalysed coupling of alkynes with allylic alcohols.210 Dienol derivatives undergo palladium catalysed condensation with propargyl carbonates in both inter- and intra-molecular fashion to produce mixtures of isomeric enals in moderate to good yield."' Similar results are obtained using vinylic diol carbonates.212 Isomerisation of secondary prop- 2-ynylic alcohols is possible on treatment with Wilkinson's catalyst in the presence of tributyl- phosphine.The nature of the phosphine is important as triisopropylphosphine affords allylic y, &Unsaturated aldehydes arise from the alcohols.213 Rhodium catalysts are also important in the silaformylation of alkynes. A number of reports in this area have been forth~oming.~'~ In related work the first example of germaformylation has been noted.215 Hydroformylation of alkynes is frequently complicated by concomitant reduction to the saturated aldehyde. However, good yields of the desired enal can be obtained using the bisphosphite ligand 8 developed for alkene hydroformylation."6 However, with non-symmetrical alkenes the regio- chemistry is at best moderate.OMe OMe p 9 0 Full details have been published on the use of dioxolanyl salts as acyl equivalents for coupling with alkynyl b ~ r a t e s . ~ ~ ~ There have been a particularly large number of reports for the elaboration of unsaturated trifluoromethyl ketones: these have involved reagents based on boron,219 tellurium220 and phosphorus.221 Fluorine aids an efficient homologation of ketones to the corresponding enal through treatment with difluoromethyllithium.222 One of the most common methods for the generation of unsaturated ketones is via the Wittig reaction. The direct reaction of a stabilised Wittig reagent with the ozonide derived from a terminal alkene is possible but slow. This reaction is markedly accelerated by the addition of triethyl- amine.223 Non-stabilised Wittig reagents afford mixtures of stereoisomers. Cis enals can be isomerised to the corresponding trans isomer on treatment with catalytic potassium carbonate and thioacetamide in DMF.224 Conversion of unsymmetrical 1,3-diketones to the corresponding P-haloenone was first reported by Piers; this method affords the more sterically hindered ketone.225 The alternative regiochemistry can now be attained in moderate yields by one of the three methods.226 ct-Functionalisation of enones is readily achieved via the Bayliss-Hillman reaction.The first enantio- selective strategy for this conversion has recently been developed (Scheme 13).227 Related a-methylene ketones can be obtained through the iodine mediated oxidation of tertiary allylic alcohols228 or through the palladium mediated carbonylative alkylation of bis-homoallenic through the reaction with acyl tetracarbonyl A similar transformation is possible Steel: Aldehydes and ketones 159+ CH3CH0 0 Me3SiSP, MeCN, -78 OC AA PhS' 50%, 90% de, 93% ee 1 mCPBA, -10 "C then 130 "c 55%.09% ee Scheme 13 5.2 a-Heteroatom substituted aldehydes and ketones The most common strategy for the construction of a-hydroxy ketones is via enolate ~xidation.~~' Improved conditions for the Rubottom oxidation of bicyclic silyl enol ethers have been claimed.232 Oxidation of titanium enolates with tert- butylhydroperoxide (TBHP) is possible: this represents the first recorded use of this particular oxidant for this tran~formation.~~~ Interestingly, with chiral ketones, modest to excellent diastereoselectivities are obtained.Fluoroalkyl analogues of Koser's reagent, P ~ I ( O T S ) ~ provide a stable convenient oxidant for the conversion of enol ethers to a-tosyloxy Allenes are oxidised to a-ketols by hydrogen peroxide in the presence of catalytic peroxytungstoph~sphates~~~ whilst in the presence of a ruthenium catalyst and an oxygen atmosphere TEMPO selectively converts primary alcohols to the corresponding a-ald01.~~~ Dioxirane oxidation of symmetrical diols affords the corresponding ket01.~~~ Homologation of an aldehyde to an a-ketol can be achieved under non- oxidising conditions through the reaction with benzotria~olylphenoxymethane.~~~ Katritzky has also introduced other substituents into these benzotriazole based acylanion eq~ivalents.~' In addition to the reaction with carbonyl groups to afford functionalised ketols they also function as nucleophiles with a range of other electrophiles, e.g.enones. The use of functionalised methoxymethane derivatives is a development of the original procedure of Trost who introduced the phenylsulfenylmethoxymethane reagent for a-methoxy ketone synthesis. Improvements in this latter strategy are obtained thorugh the use of zirconium or hafnium tetrachloride to catalyse the pinacol type rearrangement.240 In a similar vein, a-chloro carbonyl compounds may be accessed via treatment of the homologous carbonyl compound with lit hiodichloromet hylp henyl sulfoxide."' Sterically hindered ketones may be directly converted to the a-methoxyketone on treatment with a MeI-CC14-KOH combination under phase transfer conditions.242 ing a-silyloxyarylketones occurs with no loss of stereochemical integrity on treatment with trimethylsilyl triflate in DMS0.243 In an approach to the bryostatins, an a-silyloxy epoxide is selectively converted to the corresponding a-keto diol in the presence of silver tetrafluoroborate,244 whilst on treatment with BF3.0Et2 bicyclo-a,P-epoxyacrylates undergo a regioselective rearrangement to a-acyloxy spirocycl~alkanones.~~~ a-Hydroxy-acids, on treatment with a perfluoro acid anhydride, regioselectively afford the acyl perfluoroalkyl carbin01.~~~ Although the mechanism of this process has not been elucidated it parallels that of the Dakin-West reaction of N-alkyl N-acyl amino the hydroxymethylene aldose is catalysed by nickel ethylenediamine c~mplexes."~ The Wittig rearrange- ment of chiral allyloxyhydrazones provides efficient routes to enantiomerically enriched (63-90% ee) a-hydroxycarbonyl compounds.249 Hydrazones also prove to be effective chiral auxiliaries for the alkylation of protected hydroxyacetaldehydes.250 A variety of other chiral auxiliary mediated strategies for the production of a-hydroxy or a-amino aldehydes and ketones have been delineated.251 Both protected a-hydroxy and a-amino carboxylates may be selectively converted to the aldehyde or ketone.252 In this respect the reaction of a-acetoxy acyl chlorides with organomanganese reagents to afford the a-acetoxy ketone with complete chemoselectivity and minimal stereochemical degradation is particularly n o t e w ~ r t h y .~ ~ The generation of quarternary a-amino ketones through the rearrangement of fl-hydroxy imines has been rendered enantio~elective.~~ Enantiomeric a-amino aldehydes are produced in situ on reaction with the phenylmenthol containing phosphonate 9.255 Similar dynamic kinetic resolution strategies have also been employed with other aldehydes.256 The direct conversion of an alkene to an a-keto azide is possible through the use of hypervalent iodine reagents in combination with trimethylsilylazide. The stable azido iodinananes 10-12 have been introduced as more convenient Conversion of an aryl epoxide to the correspond- The rearrangement of a ketose to Y3 0 10 11 12 160 Contemporary Otganic Synthesisreagents for this transf~rmation.~~~ However, some of these compounds have explosive tendencies and the use of chromyl azide which can be prepared in situ has been advocated.258 The same authors have also reported the analogous preparation of chromyl nitrate for the synthesis of a-nitro ketone from a l k e n e ~ .~ ~ a-Nitro ketones are also accessed through the tin( 11) chloride mediated reaction of trichloro- nitromethane with acid chlorides.260 Regiospecific diazo transfer to non-symmetrical ketones can be achieved from the corresponding a-phenacyl ketones (Scheme 14).261 Such decarbonylative procedures are also found in the regioselective bromination of tertiary #I-keto esters.262 Perfect regiocontrol is exhibited in the bromination of enol borinates prepared via the hydrozirconation-acylation of vinyl b~rinates.’~~ Asymmetric bromination is possible using an acyl dithiane oxide chiral auxiliary. The product may be converted to the corresponding a-aminoketone, albeit with some loss of optical purity.zu * P h q 1.K2C03, Bu,NBr, ii. Me1 PhH, reflux C8H17 61 % N2+ C8H17 70% Scheme 14 Although the initial addition is not particularly selective, electrolytic fluorination of camphanyl enol ethers affords routes to enantiomeric a-fluoro been introduced as a selective electrophilic fluorinating agent. Comparisons with similar existing reagents indicate that this provides a more effective method for enolate fluorination.266 P-Dicarbonyl compounds undergo a very facile enol fluorination on reaction with diluted fluorine.267 The same reagent system is useful for the synthesis of a- and a,P-difluoro enones.268 The corresponding a-iodo enones can be obtained through the reaction of an enone with trimethylsilyl azide and iodine.269 a,a-Difluoro ketones are produced in the reaction of acetylenes with Bank’s fluorinating reagent, through the palladium(0)-mediated addition of iododifluoro- methyl ketones to allenes and via the treatment of a-hydroxy orthodithioesters with Bu4NH2F3 and 1,3 dibromodimethylhydantoin.z70 ethylthiolate efficiently leads to an a-keto thioether, probably via an SET (single electron transfer) process.27’ The latter can also be prepared through N-Fluoro o-benzenedisulfonimide has Reaction of an a-dibromo ketones with the use of the hydrazone methodology developed by de Kimpe; full details of these procedures which provide access to a range of a-substituted carbonyl compounds have been published.”’ Equally good yields of a-keto dithianes result from the reaction of tris (t hiomet hyl) methyllithium with esters.273 In addition, several routes to the seleno analogues have been reported.274 Strategies for the synthesis of other a-sulfur containing carbonyl groups have appeared including a-keto sulfones and thi~cyanates.’~~ The stereochemistry of the acylation of chiral phosphine oxides has been elucidated,276 whilst the use of chiral auxiliaries in the rearrangement of vinyl phosphonates to P-keto phosphonates results in a small but measurable asymmetric 5.3 Dicarbonyl compounds The oxidation of acyclic 1,Zdiols to diketones can efficiently be achieved through the action of hydrogen peroxide in the presence of a peroxy- tungstophosphate catalyst.278 Cyclic substrates are more resistent to oxidation.The reaction proceeds via the intermediacy of the corresponding a-ketol and these are also suitable substrates. TEMPO derivatives have previously been used for simple alcohol oxidation and a recent report extends the scope of this reaction to include the diol to diketone conversion. In this respect the yields obtained are better than those found using the Swern However, the latter is an effective reagent system for the production of aromatic 1,2-carbox- aldehydes. 280 The double acylation of oxalic acid units provides a number of opportunities for 1,Zdiketone synthesis.Full accounts have been published on the use of bis-Weinreb amidesZ8l and cyclic oxamides.28’ Oxalyl chloride is a suitable substrate for condensation with two equivalents of a magnesio- cuprate provided additional lithium bromide is added.283 The electrochemical acyloin reaction proceeds directly to afford the symmetrical diketone with no requirement for an additional oxidation step. If trimethylsilylchloride is added then the a-ketol may be isolated.2w Monoprotected 1,2-dicarbonyl compounds are produced in a multistep a-oxidation of a, P-unsaturated the dioxirane oxidation of 1,4-dioxenes to a-ketal aldehydes,286 and in the rhodium mediated decomposition of a,d-diazo ketones in the presence of a primary alcohol. However, the latter is only an efficient process for the synthesis of indanedi~nes.~~~ 2,2-Dialkylindane-l,3-diones are accessed via the Wittig-Horner reaction of phthalide phos- phonates.288 1,3-Diketones are generally prepared through a Claisen type strategy as evidenced in a biomimetic polyketide synthesis using a tetramethyl- glycoluril template 13.289 Unsaturated acyl electro- philes are not always efficient although the use of the Weinreb amide analogue may help.zw Steel: Aldehydes and ketones 16113 Difficulties in the condensation of ketones with perfluoroalkyl acyl chlorides can be avoided through the use of the morpholino enamine.291 Cyclobutanes are a suitable electrophilic component in the vanadium(v) mediated reaction with silyl enol ethers although tetrahydrofuran formation can compete.292 Alkylation using p-lactams as substrates provides modest diastereoselectivity at C-3.293 A general approach to 3-unsubstituted diary1 pentane- 1,3-diones is available via isoxazolines derived from nitryloxide-alkene cycl~additions.~~~ Hexane-2,5-dione is efficiently generated via the dioxirane oxidation of cis-diamino-1,2-dimethyl- cyclobutane.Whether this is a general transforma- tion remains to be seen.295 The conjugate additionhrapping of trimethylsilylbenzotriazole 14 provides a novel acyl anion for the synthesis of 2-ene-l,4-diones (Scheme 15). This sequence is general for the p-enone functi~nalisation.~~~ 1'4-Diketones are produced when enones are combined with (i) aldehydes in a photochemical reaction,297 (ii) furans in the presence of Lewis acids298 and (iii) nickel acylate complexes.299 The last of these also couple with a variety of alternative Michael acceptors such as nitro alkenes to afford other 1,n-diketones.Enhancements have been developed for the synthesis of bis-enones from cycloalkenones via a tandem ozonolysis-Wittig reaction.300 have been recorded. These compounds can now be generated using phenylmanganese chloride and a catalytic amount of amine base.303 In the enantio- selective deprotonation of ketones with chiral amide bases the effect of added lithium chloride is normally to raise the enantioselectivity and allows for an efficient 'external quench'. Whilst this effect has been probed, the use of -0.4 mole equivalents of zinc chloride is found to produce enhanced levels of asymmetric i n d ~ c t i o n .~ ~ Koga's work on the enantioselective alkylation of tetralone enolates has been reviewed.305 This substrate is also a favourite for studies on asymmetric enolate protonation for which excellent selectivities ( ~ 9 4 % ee) can now be observed.306 It remains to be seen how general these procedures are. a-Substituted ketones may also be resolved through enzyme mediated hydrolysis of the corresponding oxime acetates.307 Antibodies have been raised for the hydrolysis of enol ethers and the origin and extent of the enantioselectivities obtained have been discussed in some The same authors have also recorded the first antibody catalysed aldol reaction albeit with fairly modest levels of asymmetric i n d u c t i ~ n . ~ ~ There have been a number of developments in auxiliary mediated asymmetric alkylation.This can be achieved electrochemically via the concomitant decarboxylation of a malonic ester derivatives an an ally1 carboxylic acid.310 Two auxiliaries 15 and 16, suitable for the direct conversion into the free chiral aldehyde or ketone with minimal racemisation, have been introduced.311 Enantioselective trifluoro- methylation of an achiral ketone enolates is now a possibility using the CF; equivalent 17 developed by Umemoto (Scheme 16).3'2 0 0 i. LDA, E+ 11. H30* Bt = benzotriazde E = RCOCI, RCHO, RX, etc. Scheme 15 Finally there have been a number of develop- ments in the search for high activity and stereo- regularity in the olefin-carbon monoxide copolymerisation.301 In a related study polycarbonyl compounds are produced in the lanthanide promoted polymerisation of cycloalkenones.302 6 Reactions of aldehydes and ketones 6.1 The aldol reaction and other enolate additions The advantages associated with the use of Mn enolates, e.g.regioselective monoalkylation, etc., 15 16 Ph & TO- 41%, 42% 88 17 Scheme 16 Both alkenes and dienes can function as electro- philes in the presence of manganese acetate or CAN re~pectively.~'~ The latter is also suitable for the allylation of P-diketones with allyltrimethylsilane under neutral conditions,314 whilst in the presence of 162 Contemporary Oiganic Synthesiscobalt salts a number of compounds such as allylic alcohols function as alkylating agents.315 The various methods for alkylation of these dicarbonyl substrates have been surveyed.316 A problem with many of these enolate alkylation sequences is the competition between C- and 0-alkylation; now conditions have been refined for selective C- alkylation of P-diket~nes.~’~ Related to this, Zhao has reported an unusual sequence for the synthesis of homologous aldols in high diastereoselectivity through the tandem C- and 0-alkylation of cyclo- hexanone enolates (Scheme 17).’lS P-Keto ester dianions can effectively formed in situ through the samarium iodide treatment of bromo esters.319 Such metal-halogen exchange provides an alternative route for enolate generation and whilst samarium seems to be the reagent of choice a number of alternatives have also been employed.320 Scheme 17 Syn aldols, and therefore (2)-enolates, are efficiently produced in the absence of base when ketones are treated with 5 mol% titanium tetra- fluoride in the presence of an acceptor aldehyde.The alternative anti diastereoisomer is obtained thorugh the use of PhTi(OR)4MgBr in a thermo- dynamically controlled process (Scheme 18).321 PhTi(OPr‘),MgBr 72% 2 : 98 5 mot% TiF4 63% 68: 32 Scheme 18 Similar control of diastereoselectivity can be observed in the use of antimony salts in the addition of tin enolates to 2-chlorocyclohexanone.322 Tin enolates are also generated in a neutral free radical mediated aldol type process reported by Enholm (Scheme 19),32 The diastereoselectivity observed in aldol processes involving various other enolates, TBSO OR TBSO 0 0 OH Scheme 19 including those from a-azido ketones,324 enones (both free325 and manganese ~omplexed~’~) and P-hydroxy ketones (ald~ls),~” has been studied.Various factors which affect the diastereo- selectivity of the double asymmetric aldol reaction have explored including the stereochemistry of the chiral aldehyde, the metal enolate utilised and the nature of the /3-substituent, including the particular protecting group employed. Through careful choice of the reaction conditions it is relatively easy to produce the opposite sense of diastereoselection commencing from the same starting material (Scheme 20).328 To help account for these factors, particularly 1,3-asymmetric induction, Evans has described modified aldol transition Similar control can be realised through the appropriate choice of ligand in the chiral Lewis acid mediated aldol presumably involved in the titanium mediated asymmetric aldol reaction utilising the cheap commodity chemical, 2-methoxypropene.”’ The chiral ligand is that previously employed by the same group in the asymmetric aldol reaction of ketene silyl acetals. Palladium catalysis is also effective for the asymmetric aldol reaction which proceeds via an oxygen bound enolate rather than the traditional Lewis acid catalysed rne~hanisrn.~~’ Multistep strategies for the synthesis of enantiomeric aldol products have been reported using chiral sulfoxide~~~~ and nitrile oxide cycloadd~cts.~” Similarly homochiral P-amino ketones are obtained via the asymmetric Michael addition to cc, /I-unsaturated Weinreb a m i d e ~ .~ ~ ~ These products are also accessible through a nickel catalysed ketone-imine and the lanthanide mediated addition of enol ethers to in situ generated i m i n e ~ .~ ~ ~ These reactions may be carried out in aqueous THF. Other water tolerant or water stable Lewis acids have been aldol reactions of unprotected sugars in aqueous methanol using calcium hydroxide as a base have also been reported.339 Not surprisingly, in view of these developments, the stereocontrolled aldol reaction retains a pivotal An ene type mechanism is The no nu r ) I TBSO OR OH 0 : ! ! I t TPS = ButPh2Si R = MOM LHMDS, M F 95% 97 : 3 R = MeSi Bu2BOTf, Et3N, CH2C12 74% 55 : 295 Scheme 20 Steel: Aldehydes and ketones 163role in natural product synthesis. As examples, the reader is directed to the synthesis of oleandolide reported by Paterson and an approach to taxol@ from the Mukaiyama group.34o 6.2 Conjugate addition reactions Organocopper species retain a pivotal role in conjugate addition reactions.The complex mixed salts Li2CuX3 are excellent sources of copper(r) for use in the catalysed addition of Grignard reagents to enones.”’ As with many of these procedures the use of trimethylsilylchloride is recommended for optimal yields. Alternatively, novel mixed thio-alkoxy ligands have been introduced as joint lithium- copper chelators to enhance the reactivity of these reagents.”2 This can also be achieved through the use of Lewis acid activators of the enone system; a rhenium complex proves to be effective both chemically and ~tereochemically.”~ An asymmetric Lewis acid catalysed Michael addition of silyl enol ethers is also possible which exhibits high diastereoselectivity if not particularly high enantioselectivity .” conjugate addition of alkylaluminium reagents including the higher organoalanes to enones.Enals, however, only couple efficiently with trimethylaluminium.” Nickel acetylacetonate is also an effective promotor, being particularly suitable for sterically hindered enones.% As with many transition metal catalysed processes, the use of alkyl groups containing /I-hydrogens is not possible. Since only one group is transferred from the aluminium, studies of the effect of the additional ligands have been undertaken which show that the use of dialkylethoxyaluminium does not require any promoter. The use of trimethylsilyl chloride minimises the amount of copper catalyst required, although trimethylsilyl bromide completely suppresses the conjugate addition.” Addition of a silyl triflate promotes the conjugate addition of organoaluminates.Whilst 1,Zaddition can compete when alkyl group transfer is attempted, both alkenyl and alkynyl delivery is very efficient.348 The latter is not normally possible using classical cuprate methodology. 1,4-Addition of aromatic units to enones may be achieved via the palladium catalysed coupling of amino boronic acids with enones in the presence of antimony tri~hloride.~~ The principal focus of much of the work in this area remains absolute stereoselectivity. Chiral auxiliaries have been employed in both and n~cleophile~~’ with moderate to excellent diastereoselectivity being obtained.Greater emphasis is currently placed on catalytic asymmetric synthesis; this is also true of conjugate addition. With one exception the successful examples of such a strategy have employed stabilised anions.”* The exception is a report by Tomioka who employed the proline based phosphines 18 and 19 to catalyse the conjugate addition of Grignard derived cycano- cup rate^.'^^ Interestingly these afford the enantio- Copper also acts as an effective catalyst for the meric products to those obtained from the corresponding lithium reagents (Scheme 21). New inexpensive accessible chiral ligand systems have also been identified for the nickel catalysed conjugate addition of dialkylzincs to e n o n e ~ . ~ ~ ~ 58-98%ee 7681% 88 Scheme 21 Finally, macrocyclisation via the caesium carbonate mediated Michael reaction of enones and ynones affords good yields of the 14-membered ring ketone without the need for slow addition or exceptionally high dilution (0.01 M), as shown in Scheme 22.Whilst an attractive strategy, there is some evidence that the process can be substrate specific, particularly in relation to enone geometry. 355 J0 C+COa, MeCN rt, [o.ory I 90% Scheme 22 7 References 1 C. F. de Graauw, J. A. Peters, H. van Bekkum and 2 B. Zheng and M. Srebnik, J. Og. Chem., 1995,60, 3 P. H. J. Carlsen, C. Kjaerstad and K. Aasb0,Acta 4 H. S. Kasmai, S. G. Mischke and T. J. Blake, J. 0%. 5 J. Muzart and S. fit-Mohand, New J. Chem., 1995, 6 S. Ait-Mohand and J. Muzart, Synth. Commun., 1995, 7 S. Ait-Mohand, F. HCnin and J.Muzart, Tetrahedron J. 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