Main group organometallics in synthesis MARTIN WILLS Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK Reviewing the literature published between January 1994andJune1995 Continuing the coverage in Contemporary Organic Synthesis, 1994, 1, 339 1 2 2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.2 3 3.1 3.2 3.3 4 4.1 4.1.1 4.1.2 4.1.3 4.2 5 5.1 5.1.1 5.1.2 5.1.3 5.2 5.3 6 6.1 6.2 7 7.1 7.2 8 Introduction Group 1 Lithium Lithium amides and enolates Non-stabilised organolithium reagents Lithiated aromatic and heteroaromatic groups Benzylic and allylic lithium anions Alkenyl and alkynyl anions Anions stabilised by sulfur, silicon and other heteroatoms Group 2 Magnesium Barium Zinc and mercury Group 13 Boron Boron enol ethers, borane catalysts and alkylboranes Allyl-, allenic and alkenylboranes Hydroboration and carbonyl reduction by boranes Aluminium, gallium and thallium Group 14 Silicon Silyl enol ethers Allyl-, benzyl- and alkenylsilanes and their derivatives Other classes of silicon reagent Germanium Tin Group 15 Phosphorus Arsenic, antimony and bismuth Group 16 Selenium Tellurium References 1 Introduction As with previous reviews the emphasis will be on synthetic aspects, rather than mechanistic and structural properties, of the organometallic compounds in the following discussion.2. Group 1 2.1 Lithium 2.1.1 Lithium amides and enolates Under certain conditions, and provided P-hydrogen atoms are available, lithiated amines can act as reducing agents; this aspect of their reactivity has been reviewed recently.' The use of homochiral lithium amides in asymmetric deprotonation chemistry is now a mature area of research and most reports now detail refinements and improvements to known systems.A striking recent application of this methodology has been in the asymmetric ortho-lithiation of certain activated arene-chromium tricarbonyl complexes, where enantiomeric excesses (ee7s) of up to 90% have been recorded.2 Lithium enolate chemistry is pivotal to organic synthesis and a comprehensive coverage would not be possible in a review of this type. However attention will be drawn to recent developments in the area of asymmetric protonations of racemic enolates, which have in some cases been refined to give ee's of up to 98%.3 With the aid of an appropriate chiral ligand, similar selectivities may be achieved in alkylation reactions of certain c~mpounds.~ 2.1.2 Non-s tabilised organolithium reagents Due to their high reactivity, organolithium compounds are rarely used in catalytic asymmetric reactions, since reaction acceleration is difficult to achieve.This feature is reflected in the report by Denmark on the asymmetric addition of alkyllithiums to imines catalysed by diamines, in which ee's of up to 82% are achieved, but only when a stoichiometric amount of ligand is empl~yed.~ Whilst halide-lithium exchange reactions remain the predominant method for formation of complex organolithium building blocks,6 the use of lithium metal, together with a catalytic amount of a polyaromatic, is gaining popularity. In a recent development it has been demonstrated that aryl sulfones can serve as suitable precursors for this ~hemistry.~ The same Barbier-type process can be achieved using sonochemical methods.' In recent years intramolecular cyclisations of organolithiums onto unactivated double' or triple" bonds has been developed into a versatile and reasonably general procedure.In one example a very simple diene synthesis has been achieved Wills: Main group organornetallics in synthesis 201(Scheme l).'O" Related cyclisations onto activated multiple bonds are also synthetically valuable, especially when the process can be achieved in a tandem sense by setting up an appropriate sequence of five- and six-membered rings. This has been illustrated by the stereoselective conversion of iodide 1 into the bicycle 2 upon treatment with butyllithium. ' ' Reagents: i, 2.0 eq.Bu'Li, C5HI2, Et20, -78 "C to r.t.; ii, H30t Scheme 1 r( co2Bu' 1 2 3 Lithium anions may be created adjacent to heteroatoms by a variety of methods. In a large scale (2.2 kg) example of the 'reductive' method, an excess of lithium metal is employed to generate 3 and subsequently 4 upon reaction with the appropriate chiral aldehyde." This synthesis clearly underlines the value of such methodology to process development as well as to small scale synthetic work. In other cases, however, the process of lithium-bromine exchange via the use of an alkyllithium is fav0~red.l~ In some cases this can be a stereoselective process, as illustrated by the low temperature reaction of 5 with butyllithium to give predominantly the isomer .-.6, which was trapped as a Gc, T 7 1 p : Bn2N Br HO 4 5 74- TBDMS-O TBDMS-O o\B,o &Br W B r 6 7 TBDMS-O OH 0 +ok 8 boronic ester derivative 7.IJb This reaction formed the basis for the synthesis of the bryostatin subunit 8 via reaction with the dianion of tert-butyl acetoacetate. The corresponding reaction of butyllithiums with alkyl chlorides does not result in lithium-chlorine exchange; deprotonation adjacent to the chlorine is favoured. This process may also be employed to synthetic ad~antage.'~ Lithiation may be achieved by deprotonation a- to a nitrogen atom;I5 however some form of activation or a directing group is invariably required. In some cases polyamines, which are often employed to activate alkyllithium bases, can direct their own self- lithiation.In some cases this can be a troublesome side reaction, as illustrated by a report of tetramethylethylenediamine (TMEDA) lithiation,I6 but may also be employed to useful effect, for example in a methylene transfer reaction (Scheme 2).17 Carbamates are perhaps the most widely used directing groups for lithiation adjacent to nitrogen,'* and a full paper has appeared describing formation and applications of enantiomerically enriched complexes such as 9. These valuable homochiral building blocks are formed by the action of butyllithium complexed with a chiral ligand such as the diamine sparteine." Applications of these and related compounds have been extensively explored; however a very attractive recent addition to the repertoire is a very valuable palladium coupling with aryl halides to give the 2-aryl derivatives Directed lithiation adjacent to a nitrogen atom may also be achieved by using a complex with carbon disufide, as in 11, which collapses back to the amine upon work-up of the reaction.21 Reagent: i, pentane, 0 "C Scheme 2 9 10 11 Trialkyltin-lithium exchange is another of the popular methods for formation of lithiated anions adjacent to nitrogen." Rather milder conditions are required to achieve this than for direct deprotonation, which has obvious advantages.This 202 Contemporay Organic Synthesisprocess has formed the basis of an interesting cyclisation reported by Coldham, in which a five- membered heterocycle formation is terminated by re-addition of trimethyltin (Scheme 3).” As well as the bonus that is afforded by the further manipulation of the trialkyltin group (for example to give an acetal), the process also benefits from the fact that only a catalytic amount of methyllithium is required. Reagent: i, MeLi Scheme 3 Formyl anion equivalents22 are of great use in synthesis and will feature at various points throughout this report.Less common however are the nitrogen equivalents - imines lithiated at the a-position such as 12.24 Such compounds may be simply generated by the addition of tert-butyllithium to the appropriate isonitrile and, in the example referenced here, add to carbon monoxide and then cyclise in an intramolecular sense onto the aromatic ring to form indoles. The trifluoroacetimidoyl lithium compounds 13 may be generated from the corresponding iodides using butyllithium25“ and a related compound has been prepared by a similar treatment of a trialkylstannane precursor.25’ 12 13 14 n =1,2 15 n =1,2 Much of the discussion above is also applicable to the preparation and use of lithium anions adjacent to oxygen.Reductive methods using lithium metal and catalytic amounts of a polyaromatic are again popular, and have been successfully employed for the formation of lithiated tetrahydrofurans and pyrans 14 from the precursors 15 in high yields.26 Useful chiral building blocks such as 16 are available in the same way.27 Whatever the method of generation, anions adjacent to oxygen atoms have been employed extensively in Wittig rearrangements to great effect,28 as illustrated by the impressive ring expansion of 17 to give the bicyclic product 18 (the 16 17 18 lithiated species is generated from the trimethyltin precursor).’& Hoppe has reported further results from his studies on the asymmetric directed lithiations of carbamates using the chiral base sparteine as a directing group.29 Such reactions show remarkable dependence on the nature of the deprotonation conditions and the nature of additives.Reaction of 19 with 1.5 equiv. of sec-butyllithium in ether at -78 “C involves a directing effect by the dibenzylamine group to give the lithiated species 20. In contrast, use of the same conditions in the presence of 1.5 equiv. of (-)-sparteine gives the regioisomeric complex 21 (sparteine is omitted for clarity), presumably due to the overriding directing effect of the chiral diamine-alkyllithium complex.29a 0 - Cy2N K O ~ o ~ NCy2 NBn2 0 19 20 X = L i , Y = H 21 X = H .Y = L i 2.1.3 Lithiated aromatic and heteroaromatic groups Of all the functional groups known to be effective at directing the ortho-lithiation of aromatic rings, methoxy and amide groups are two of the most effective. However even a catalytic amount of TMEDA can generate a dramatic rate increase in this process, an effect which has been studied in detail recently.” The presence of a para-fluoro atom has also been shown to provide a dramatic rate enhancing effect, presumably due to activation via inductive electron withdrawaL3* Bromine-lithium exchange provides a milder alternative to deprotonation and is the method of choice provided a suitable substrate is available.In the total synthesis of balanol, Nicolaou employed such a process to convert ester 22 to the ketone 23 via an intramolecular reaction initiated by treatment with b~tyllithium.~’ After oxidation with TPAP and further steps, 23 was converted to the side chain of the synthetic target molecule. In another intramolecular example, rapid bromine-lithium exchange outpaces attack by phenyllithium on the epoxide in 24, allowing intramolecular ring opening to be achieved to give the product 25.33 The relatively facile 2-lithiation of furan rings has been studied in some detail. This process has been employed recently in a key step in the total synthesis of salinomycin, where fragment 26 was coupled cleanly with another of equal complexity to provide the C( 11)-C(30) portion of the target molecule.34 One-pot furan lithiation and acylation may also be achieved using the sonochemical Barbier reaction in Wills: Main group organometallics in synthesis 2030 OBn qco%oTp.Br OBn OBn 22 23 24 25 26 ph# + PhCO21i+ - i Ph&Ph OH OH 0 Reagent: i, Bu'CI, TMEDA, THF, 3 9 , r.t., 15 min. Scheme 4 which the lithium salt of a carboxylic acid is irradiated in the presence of tert-butyl chloride and lithium metal, presumably resulting in in situ formation of tert-butyllithium (Scheme 4).35 Direct thiofuran lithiation favours the 2-position; however 3-lithiothiofuran my be prepared from the appropriate bromide precursor.36 The use of thiofuran as a 4-carbon fragment (via exhaustive reduction to the hydrocarbon) is well established. An excellent example of this has recently been described in which the coupling of 2-lithiothiofuran and bromide 27 provides a key step in the synthesis of the C2 symmetric target (+)-xestospongin A 2tL3' The thiofuran in this case provides the atoms in the two chains linking the heterocyclic units.Treatment of tetrabromothiofuran may be selectively controlled so that one bromide is predominantly exchanged for lithium, as described in some detail by I d d ~ n . ~ * CI 27 28 LiQ 29 Lithiated pyridines are valuable synthetic intermediates which have been the subject of a good deal of detailed studies recently. A good example is the use of 34ithiopyridine 29 to provide the heterocyclic ring in a recent short synthesis of epibatidine 30.39 Comins4' has reported further results from his studies on directed lithiations of pyridines using lithiated hemiaminals, which may be introduced via reaction of the lithiated pyridine with a formamide (Scheme 5).In the sequence illustrated, which is part of a camptothecin total synthesis, further lithiation is achieved directly, 30 1 iv, v I CI &OH 0-0- Reagents: i, Bu"Li; ii, Me2NCH2CH2N(Me)CHO; iii, Bu"Li; iv, 12; v, NaBH4. H20 Scheme 5 followed by iodination and then reduction of the intermediate aldehyde. In a related sequence, the synthesis of parvifoline has been achieved, although not on a pyridine ring in this case.41 Finally in this section, the synthesis of atpenin B, 31, via a sequence of four sequential lithiations of 2-chloropyridine, working clockwise around the ring as drawn, is highlighted.42 2.1.4 Benzylic and allylic lithium anions Alkylations of unsymmetric allyllithium compounds can occur with low regioselectivity if the steric differentiation between the 1- and 3-positions is not great.A useful solution to this problem is to perform the alkylation in an intramolecular sense. This idea is illustrated by the formation of allylsilanes 32 via a [1,4]-Brook rearrangement of the silyloxy precursor anion 33, which may be formed by either reduction of an allylic thioether, as in this example,43 or tin-lithium exchange.44 In either case the anti product dominates (>90% this isomer) and the resultant double bond is invariably 204 Contemporay Otganic SynthesisOH 0 OH Si(Bu’)Ph2 P h A : L MeOANAOH 31 32 Li+ OSi(Bu’)Ph2 Li+ I - Ph- 33 34 35 36 37 38 trans irrespective of the geometry of the starting material.Katritzky has reported further examples of the applications of allylic anions based on benzotriazoles 34. Such reagents are highly versatile and may be used to prepare cyclopropanes or unsaturated ketone derivatives depending on the exact conditions empl~yed.~’ chloromethyl substituted aromatic or heteroaromatic compound generally results in deprotonation to form a benzylic anion. Such anions may subsequently be employed in the formation of epoxides upon reaction with ketones or aldehyde^.^^ The reduction of chloromethyl ketones with lithium metal and a polyaromatic, on the other hand, provides an excellent method for the formation of non-stabilised benzylic anions, which are often otherwise difficult to prepare.47 When there are activating or directing groups on the aromatic ring, such as a phosphate48 or an amide,49 direct benzylic deprotonation can be achieved under relatively mild conditions.When (-)-sparteine was used in collaboration with an alkyllithium base for the deprotonation of 35, an asymmetric complex 36 was formed. The enantioselectivity of alkylation of 36 shows a remarkable dependence on the nature of the alkylating agent; 37 (up to 97% ee) is the product when alkyl tosylates are used whereas the enantiomer 38 (up to 92% ee) is the product when alkyl halides are employed.49 Heteroallylic anions featuring a central nitrogen atom have been developed into valuable synthetic reagents in recent years5’ Pearson has reported a number of inter- and intra-molecular cyclisation reactions directed at the synthesis of alkaloids which feature these reagents (Scheme 6).’O“ Trialkyltin- lithium exchange appears to be the method of choice for their generation.A related series of reagents featuring an additional stabilisation by an enolate has also been reported.” The reaction of a strong base such as LDA with a *‘\ 1- MOM Ar 80% yield Reagent; i, 2.1 eq. Bu”Li, THF, -78 OC, 1 h. Scheme 6 2.1.5 Alkenyl and alkynyl anions The formation of alkenyllithiums by direct deprotonation is only efficient if a suitable activating” or directing group is available to assist the reaction; if not then a reductive method (vinyl chloride, lithium powder, catalytic polyaromatic c~mpound)”~ or a trialkyltin-lithium exchange methods4 may be used.Of all the possible activating groups, a-alkoxy functions are especially effective at promoting deprotonation at vinylic carbon atoms.” Several examples of the lithiation of enol ethers and related materials have been reported recently. Applications of diverse alkyllithium species thus formed, represented by 39,51a*h 40”“ and 4l5Id have also been described. The difluoro substituted reagent 42 has been the subject of considerable recent interest. In a recent paper the tandem reaction of 42 with two carbonyl compounds, reacting first as a vinyl anion equivalent and then as an enolate anion, has featured.” 39 40 41 42 Vinylic anions have seen many applications in organic synthesis. The reaction of 1 equiv. of 43 with cyclobutenedione 44 is a key step in the synthesis of isochromaquinones; a ring expansion of product 45 gives the required quinone addition-rearrangement sequence was used by Paquette in the synthesis of a tricyclic natural produ~t.’~ Lithiated dihydrofurans, e.g.46, provide useful building blocks for complex synthetic targets.” Upon reaction with cuprate 47 and a subsequent ring opening reaction and methylation, the C(16)-C(23) region of FK506 48 is prepared.57u Perhaps one of the most exciting applications of vinyl anions however has been in the area of Taxol@ was the reaction between 49 and 50 (the latter formed by a Shapiro reaction of the sulfonated hydrazone precursor) to give, in 85% yield, adduct A similar A key step in the Nicolaou synthesis Wills: Main group organometallics in synthesis 205, , OTIPS 43 i i 46 49 R' R2 G: 44 R' R2%o.OTIPS 45 I OMOM 47 48 50 51 5L5' In another synthetic approach, a vinyllithium was employed to set up an intramolecular Diels- Alder reaction in a very concise sequence leading to the Taxol@ ABC ring Alkynyl anions have also found many applications in synthesis, one of which has been as a building block in the spiroketal subunit of milbemycins.60 An impressive enantioselectivity (up to 97%) was achieved in the addition of a lithiated 2-acetylenic pyridine to a heterocyclic electrophile using a lithiated quinine to provide the directing effect (Scheme 7).61 cdio R Li R = i 93% - Reagent: i, quinine, Li, THF, -25 "C Scheme 7 2.1.6 Di- and tri-lithiated anions In the presence of a suitable directing group, dilithiated dianions such as 52 may be prepared by direct deprotonation.Whilst it has always been assumed that the directing group was in some way responsible for directing the base to the benzylic position, it is only recently that direct evidence for this has been obtained.62 Related compounds 5363 and 5461 featuring further additional stabilisation from a sulfone group have also been reported. In particular these reagents have been employed in the synthesis of nitrogen heterocycles and lactones respectively. Without the additional stabilisation or directing effects, preparation of dianions such as 5565 and 5666 generally requires an alternative approach. In most cases a variation upon the reductive method is favoured, chlorinated precursors may be employed as the starting materials6576Q or, for compounds of type 56, aziridines.6@ The reductive cleavage of a sulfide in an intramolecular sense was employed to create the dianion 57.67 Li 0 pTolS02 Li NLi 1 Li OLi Ph ANA Me NLiMe 'Ph 52 53 54 LiJR2 L i ~ R , SLi Li R 55 56 57 The lithium salt formed by the reaction of lithium methyl(meth0xy)amide with an aldehyde serves to protect the sensitive functional group from attack by nucleophiles.In one recent example of the use of this strategy a further deprotonation was undertaken to give dianion 58 which was then converted to the ally1 borane 59. After work-up of the reaction and regeneration of the aldehyde an intramolecular addition reaction completed the synthesis of target molecule 60.68 Noteworthy in this sequence is the fact that all the transformations, from the precursor to 58 to target 60, were carried out as part of a one pot process.0-Li 58 59 60 Dianions in which one or more of the anions is located on an sp2 carbon atom may be created most readily by exchange reactions, and in particular the exchange of trialkyltin groups for lithium using an alkyllithium base has proved to be the most effective method. Allylamine derivatives of general structure 61 may be prepared by such a strategy.69 Presumably 206 Contemporary Organic Synthesisthe trialkyltin precursor 62 has a finely balanced reactivity so that the exchange does not precede deprotonation at nitrogen, as is often a problem in bromine-lithium exchange reactions. A number of related trianionic compounds such as 63, prepared by similar methods, have been rep~rted.~' 61 R = alkyl, TMS 62 R = alkyl, TMS 63 64 Dilithiations of aromatic compounds are generally less troublesome, and may usually be achieved with direct reaction with a healthy excess of alkyllithium base.71*72 Whilst directing groups such as carbamates are well known to promote this type of lithiation71 carboxylic acid salts, traditionally themselves rather prone to nucleophilic attack, can under certain conditions promote ortho-lithiation reactions to give, for example, 64.72 2.2 Anions stabilised by sulfur, silicon and other heteroatoms The configurational stability of anions adjacent to sulfur in dibenzyl sulfide has been investigated by Hoffman, who has found that racemisation begins to occur at very low temperature^.^^ Whilst this rather limits applications of such compounds to asymmetric synthesis, there is sufficient stability to permit very low temperature ( - 100 "C) intramolecular reactions to take place in a stereoselective manner (Scheme 8).74 MEMO S-Ph MEMO SH __c Reagent: i, Bu"Li, -100 OC, 1 h Scheme 8 In the example shown the reaction is believed to proceed with essentially 100% inversion of configuration.The rather more configurationally stable anion 65, flanked by both sulfur and silicon, may be formed directly from the enantiomerically pure precursor using sec-butyllithium activated by TMEDA ; both the deprotonation and subsequent reaction of this anion with MeOD proceed with retention of c~nfiguration.~~ Anions stabilised by two sulfur atoms are very important in synthetic chemistry due to their value as reverse-polarity reagents.76 A lithiated dithiane has been employed in the total synthesis of FK506.7Q Further examples of lignan syntheses facilitated by the stereoselective additions of anions such as 66 to a$-unsaturated-d-lactones have been rep~rted.'~ Allylic anions stabilised by sulfur such as 67 react cleanly and regioselectively with epoxides 68 to give adducts which cyclise (to 69).A short \ I N. 65 66 67 SPh 68 69 70 series of transformations completes the synthesis of a,P-unsaturated-&lactones 70 for which they were r e q ~ i r e d . ~ ~ Allylic anions stabilised by sulfones rather than sulfides may be employed for the synthesis of enones in related proces~es.~"~ Whilst the reaction of 67 with 68 was regioselective due in part to the effect of the methoxy group, addition a- to the sulfur atom is often observed.If this is not the required isomer then it is possible to rearrange the adduct via a 1,3-shift promoted by heating to 160 "C in xylene in the presence of diphenyl disulfide (Scheme 9).79 i,ii - m S P h ox HO Reagents: i, Bu"Li, TMEDA, HMPA, THF, -78 "C+ 0 "C; ii, (PhS)2, xylene, 160 "C Scheme 9 Lithium anions adjacent to sulfoxides are important reagents for asymmetric synthesis because the sulfoxide group may in principle be resolved into enantiomers. Several applications of such anions have been reported recently, and a full paper on the synthesis and reactivity of homochiral 1,3-dithiane-1,3-dioxide 71 has appeared.Anions of 71 react with high diastereoselectivity with aldehydes ( > 95 : 5 ) and may be cleaved to a-alkoxy esters using a short sequence of reactions featuring a Pummerer reaction at a key point." Addition of the anion 72 to the cyclic nitrone 73 proceeds with a Me0 0- 71 72 73 Wills: Main group organometallics in synthesis 207face selectivity of 96 : 4, the highest yet achieved in this type of reaction. The use of other sulfoxides, such as lithiated methyl p-tolyl sulfoxide, has already been reported to give selectivities of up to 92 : A more unusual application is the ring opening of either diastereoisomer of ketal74, to give 75 as the major product, upon treatment with LDA. This strategy, the stereochemistry of which is controlled entirely by the sulfoxide, provides an alternative to enzymatic differentiation of meso- diols.82 Sulfoximines such as 76 also feature robust stereochemical centres and have found many applications in asymmetric synthesis. A full paper has appeared on the synthesis and uses of 76 itself,83 whilst conjugate addition reactions of the related compound 77 to enones have also been described.In the latter example the highly diastereoselective reaction gives 78 as the major product isomer.84 , NpTs Ph, ,-Li !.. Ph O/ /s; 'NSi(But)Ph2 e s * N p T s , .+ Ph I \\ LI - 76 77 78 Anions adjacent to sulfones 79 are generally prepared by direct deprotonation but can in some cases be formed by reductive methods.85 Such anions have been widely employed in synthesis and appear particularly compatible with synthetic approaches to large complex target molecules.Recent applications include key carbon-carbon bond forming steps in the synthesis of rapamycin, which features epoxide opening by a sulfone anion86 and aplyronine A.87 In the latter example three important bonds are formed between large fragments of the target, one by a Julia olefination process, the others by displacement of a triflate and an iodide respectively by sulfone anions. Lit hiated sulfones which form part of a three membered ring, e.g. 80, have been substituted by a range of electrophiles and then employed to form alkenes by extrusion of sulfur dioxide.88 A one pot process permits the synthesis of allylic alcohols 81 from lithiated j-silyl sulfones 82, which therefore acts as a vinyl-isoprenyl anion equivalent.89 K PhSO2-R - Li+ Li 0 2 79 80 81 R', R2 = H, alkyl Allylic sulfones may be prepared very readily by deprotonation and display a versatile reactivity pattern.Alkylation of 83 with isoprenyl bromide furnishes 84, a convenient precursor of a Diels- Alder reagent for apoyohimbine syntheskgO In another application a sequence of epoxide opening reactions was employed to form a key building block of brefeldin A in an impressive one pot process (Scheme Reagent: i, BuLi, THF, -78 "C to r.t. Scheme 10 Silicon stabilised anions have not been as extensively investigated as the sulfur analogues; however some very valuable processes have been developed. The reaction of 85 (formed by lithium metal-polyaromatic reduction of the a-sulfide) with addition to give 86.Oxidation by a conventional method then completes a very effective synthesis of enantiomerically pure cis-diol 87.92 Other silyl stabilised building blocks include the heterocycle 8893 which was used for the synthesis of epoxy diols and the silacyclopentane 89, a starting material for the synthesis of y-hydroxy ketones.94 adjacent anions and applications to alkene formation methodology are rather too numerous to comprehensively feature in an article of this type. Attention should be drawn however to the recent studies of the reactions of homochiral derivatives of this type such as 90, lithiation of which, followed by reaction with an aryl sulfonyl azide, gives 91 in high stereoselectivity. Azides of general structure 91 may be converted via a short sequence to the corresponding enantiomerically enriched a-amino Numerous phosphorus derivatives stabilise SiPh3 OH SiPha PhALi Ph 4Ph Ph 85 86 87 U I \i PhS02 $,,SiR3 Ma2cd I so2 Me02C Li 88 89 90 82 83 84 91 92 208 Contemporary Organic Synthesisphosphonic acids.95 Related allylic anions 92 have also been reported, and display remarkably high selectivities in addition reactions to ct,P-unsaturated Finally, in this section, an intriguing report has appeared describing the deprotonation of racemic phosphine oxide 93, followed by asymmetric reprotonation of the anion 94.Use of the chiral amine 95 to supply the proton returns enantiomerically enriched 93 in up to 83% ee, which can be increased to over 100% by recry~tallisation.~~ Very few examples of deracemisation methodology of this type have been reported.0 95 93 94 3 Group2 3.1 Magnesium Reviews have appeared recently describing the reactions of alkylmagnesium compounds in gene~al,~' and also the effects of alkylzirconium species on Grignard reagents in parti~ular.~~ necessarily be dominated by the enormously versatile Grignard reagents, and this article is no exception to this. One feature that makes such reagents attractive to synthetic chemists is their applicability to stereoselective addition reactions. The reaction of phenylmagnesium bromide with dimine 96, for example, results in highly selective formation of the useful protected diamine 97.'" Additions of Grignard reagents to pyridinium salts bearing chiral directing groups are highly stereoselective provided the correct substitution pattern is present on the heterocyclic ring, i.e.3-trialkylsilyl-4-methoxy. lo' Such reactions have been employed extensively by Comins for the asymmetric synthesis of alkaloids; the representative example Any review of organomagnesium chemistry will 96 OMe H H 81 Reagents: i, Me(CH2),,MgBr; ii, H30+ Scheme 11 shown in Scheme 11 features the key step in the synthesis of ( - )-solenopsin An ally1 Grignard addition fulfils a key role in a reported synthesis of the zaragozic acid-squalestatin core model structure 98 from lactol99."' Following the addition of the allylic anion (to the hydroxy aldehyde), the resulting alcohol is oxidised to the ketone level and a careful acid catalysed cyclisation reaction leads to 98. BnQ ,OPMB MBq8F?oBn -d I \ OTBS 98 99 Another target molecule which has excited a great deal of recent interest is that class based on the dynemicin structure.Alkynyl Grignard reagents have played an important role in establishing the enediyne structure in these corn pound^.'^^ In the example shown in Scheme 12 the introduction of the unsaturated bridge is completed by an acid catalysed cyclisation of the dicobalt hexacarbonyl derivative,lok a strategy also successfully applied to the synthesis of the related calcheamicins. . m g q LOTHP Reagent: i, AdOCOCl Scheme 12 Y OMe The use of chiral ligand 100 to modify the reactivity of Grignard reagents with aldehydes gives only modest enantiosele~tivities.~~~ Rather more interesting however is the remarkable observation that the ee induced increases with temperature (Scheme 13), a rare but not unknown phenomenon.Modest to good ee's (65-80%) were also obtained in the titanium-chiral diol mediated reaction of certain Grignard reagents with esters, a process which gives chiral cyclopropanes as product^.''^ The nickel catalysed reaction of cyclopropyl Grignard reagents with dithianes results in the formation of 1-substituted b~ta-1,3-dienes."~ Whilst Grignard reagents are usually formed from alkyl halides and magnesium metal, transmetallation can sometimes be a viable alternative. Hoffman has examined the stereoselectivity of the formation of derivatives 101 Main group organornetallies in Jynthesis 209phyN*N<h H F M g B r 1 00 101 OTMS I 7- 1 02 -40 "C : up to 9% e.e. 35 "C : up to42% e.e.Reagent: i, 100 Scheme 13 of gem-diiodides 102 formed upon reaction with isopropylmagnesium bromide.107 The conjugate addition reaction of chiral amines with unsaturated esters has been extensively studied by Davies, who has concentrated on the use of lithium amide nucleophiles. It appears that excellent results may also be obtained when the corresponding magnesium reagents are employed."' Intramolecular cycloaddition reactions often proceed with excellent diastereoselectivity, an advantage over intermolecular reactions which are often less selective. This disparity can be rectified by connecting the two reagents in the latter reaction using a temporary 'tether' group. Stork has reported that an alkenyl alkoxy magnesium tether can be used effectively in this capacity: 103, formed in situ by the reaction of an alkoxide with vinyl magnesium bromide, cyclised readily to 104.'09 R'TBaC' R2 103 104 105 3.2 Barium Ally1 barium reagents 105 have benefitted from a considerable level of recent research activity due to their high regioselectivity in addition reactions to electrophiles."' Such compounds are generally prepared by the reaction between an activated form of barium metal and the allyl chloride.A very comprehensive full paper has recently described their use in addition reactions to aldehydes and in conjugate addition reactions to enones. Of particular note are: (i) the consistent observation of addition to the least hindered terminus of the allyl group, (ii) the full conservation of double bond geometry and (iii) high selectivity for 1,4- over 1,2-addition ( > 99 : 1).3.3 Zinc and mercury Tremendous recent progress has been made in organozinc chemistry, thanks mainly to the efforts of the Knochel group, who have developed methods for the preparation of several classes of functionalised zinc reagents."' Recently reported methods include the reactions of alkyl bromides with either diethylzinc"' activated by copper(1)- manganese(I1) or zinc metal activated on titanium di0~ide.l'~ Benzylic zinc reagents, which are somewhat more difficult to prepare than alkylzincs, have been made in good yields from the bromides using an electrochemical meth~d.''~ Organozinc derivatives of a-amino acids such as 106 have been the subject of particular attention in recent years. Of particular note, in addition to versatility in reactions, is the compatibility of the zinc reagent to the usual protecting groups associated with amino acid chemistry.The reagents are configurationally stable and the nitrogen atom remains protonated throughout the sequence of reagent formation and during nucleophilic reactions. Jack~on"~ and others have reported full details of much of his communicated research in this area as well as new applications including palladium catalysed coupling reactions with aryl iodides116 and cc,P-unsaturated acid chloride^"^ to give 107 and 108 respectively. Further examples of palladium catalysed coupling reactions will feature throughout this section. The preparation and reactions of closely related, configurationally stable organozinc reagents of type 109 have been reported by Knochel.' '' COpBn ArYozBn NHBoc 0 COzBn I Z n p NHBoc 106 107 108 0 A Z n E t / K < ZnI 0 NH 109 110 Allylzinc reagents may be prepared by the reaction between diethylzinc and either an allyl palladium c~mplex"~ or a benzoyl protected allyl alcohol.120 In the former example, reported by Julia, an allyl sulfone was employed together with an appropriate source of palladium(0) to supply the allylic complex which then formed the allylzinc 110 in an in situ process.Reactions of 110 with carbonyl compounds were described. In the latter process (Scheme 14), which also featured stereoselective reactions with carbonyl compounds, a formal polarity reversal of the n-ally1 group was achieved.I2' A further development of allylzincs such as 111 is for the diastereoselective carbometallation of 210 Contemporary Organic SynthesisQ- TMS C5Hll leading to 118.'23 The resulting alkylzinc may then be quenched upon acidic work-up or employed in .OBz - i EEnQ - pph] Zn---0 further reactions with electrophiles.Since its first report this reaction has proved to be very versatile and may be applied to cyclisations with triple disubstituted tetra hydro fur an^.'^^ Oppolzer, who has successfully employed a palladium catalysed process to assist in situ formation of precursors 119 to intramolecular zinc- ene reactions from allylic acetates 120. Cyclisation again favours the cis-products 121, which may again be quenched by acid or further reacted with electrophiles."' and to the stereoselective formation of cis- A related cyclisation has been investigated by I TMS C5H1 1 QOBu u n 4 , Reagents: i, Etgn; ii, PhCHO Scheme 14 Li ZnBr I 111 112 113 vinyllithums.For example; reaction of 111 with 112 gives the gem dimetallated adduct 113 and subsequently the aliphatic derivative 114 upon quenching with aqueous acid.121 Several examples have recently been reported by Normant, who has proposed that the stereochemical control is the result of reaction via a transition structure such as 115. In certain cases intermediate 113 can be converted effectively to cyclopropane derivatives, again with control of stereochemistry.'22 Organozinc compounds also make excellent substrates for intramolecular cyclisation reactions. Building on the work described in the previous section, Normant has examined cyclisations of trialkylsilylalkynes such as 116; deprotonation with an alkyllithium and zinc-lithium exchange results in formation of the metallated allenic species 117 which then undergoes the intramolecular reaction M 119 Y = C(S02Ph)2, NTs, M = ZnEt 121 Y = C(S02Ph)2, NTs 120 Y = C(S02Ph)2, NTs, M = OAC The approach taken by Knochel to intramolecular cyclisations of alkylzinc reagents onto double bonds requires the use of a nickel(I1) ~ata1yst.l~~ In the representative example selected (Scheme 15), the stereoselective formation of a tetrahydrofuran ring results from a concise sequence of reactions.127u It is also noteworthy that the enantiomerically enriched starting material in Scheme 15 was itself formed by an asymmetric addition of a dipentylzinc to an a,/?-unsaturated aldehyde.L -1 1 ii, 55% OHC, C5H11 QOBu Reagents: i, Et2Zn, Lil, cat. Ni(a~ac)~, THF, 40 "C; ii, 02, TMSCI, THF, -5 "C 114 \ OMe 115 One example of a catalysed (usually by -0Me 116 palladium) coupling reaction of an organozinc has Me0 TMS TMS 117 118 already been described in this section? l6 However the literature is replete with further examples of this valuable class of reaction. In general arylzinc derivatives 122 are most commonly prepared by exchange with aryllithium reagents, which in turn originate from directed aromatic metallation'** or a halide exchange process.129 Reaction partners in Wills: Main group organometallics in synthesis 21 1125 such processes are commonly aryl halides, vinyl halides, acyl chlorides and allylic halides.129~130 In some cases the use of arylzincate reagents is favoured, one advantage being their ease of formation directly from the aryl iodides upon reaction with Me3ZnLi.13' Vinylzinc reagents 123 react in an analogous fashion but benefit from the additional benefit of ease of formation from the alkyne precursor^.'^^ The reactions of vinylzincs with allylic bromides, with or without palladium catalysis, have been described in of palladium catalysed couplings of unsaturated organozinc reagents has generated some powerful methodology. For example sequential reaction of an alkynylzinc and then an allenylzinc with 124 provide a means for the effective synthesis of the complex unsaturated product 125.'34 asymmetric catalytic dialkylzinc addition reactions to aldehydes (Scheme 16) has continued to grow unabated.Noyori, who first reported the rate enhancing effect of an amino alcohol derivative on this reaction less than a decade ago, has reported an ab initio study of the reaction135 and a very detailed account of the remarkable non-linear chirality transfer effects which are 0b~erved.l~~ A comprehensive account of all the new ligands reported within the date range of this account will not be attempted; however representative examples and novel applications will be highlighted. The combined use The number of examples of ligands for chiral ligand 0 phKH + Et2Zn seetext Ph Scheme 16 Starting first with new catalysts, the results of which are summarised in Figure 1, amino alcohols 12613' and 12713* are reported to give ee's of up to 68 and 96% respectively for the prototype reaction shown in Scheme 16.Whilst this suggests that pyridylamines are rather poor catalysts, rather better results have been obtained using the slightly more complex alcohols 128139 and 129,I4O which furnish ee's of up to 93 and 88% respectively. The exact contributions of each of the chiral components in 129 to the overall selectivity is not fully delineated; however the current enthusiasm of researchers for 126 (up to 68% ee) H O A P h Ph 128 (up to 93% ee) 127 (up to 97% ee) Ph 129 (up to 88% ee) 132 (up to 94% ee) 130 1 3 1 u (up to 94% ee) (up to 83% ee) Ph, Me 7+ 0; ,Ti(OP+), Tf 133 134 (up to 94% ee) HS 0 (up to 100% ee) Figure 1 Maximum enantioselectivity for the reaction shown in Scheme 16 catalysis by chiral oxazolines essentially ensures their inclusion in most applications.The use of amino alcohol 128 to control the addition of alkynylzinc reagents to aldehydes gives slightly better results than with dialkylzincs: up to 95% ee.I4l Further reports have appeared on the use of polymer supported chiral amino alcohols in this application, some of which give results which are almost competitive with the homogeneous reaction^.'^^ Organometallic reagents containing n-complexed metals can introduce an extra steric or stereochemical element to a ligand which can improve their catalytic properties. Referring again to the prototype reaction of Scheme 16, the chiral ferrocene derivative 130 generates inductions of up to 83% ee.143 Certain chromium tricarbonyl derivatives of chiral amino alcohols have also been examined and found to be slightly better than the uncomplexed reagents.lU However perhaps the most interesting new reagent in this class is the selenium derivative 131 of ferrocene, which can give ee's of up to 94% for the prototype ~eacti0n.l~~ Whilst rather more complex than the simple ligands with which this work is normally associated, results of this type help to expand the horizons of this important asymmetric process.212 Contemporary Organic SynthesisReplacement of the oxygen atom in the asymmetric ligands with sulfur has been the subject of some attention. Whilst the change is a logical one given the need to coordinate to zinc, slight but important improvements to ee's have only been observed for a limited number of cases.Van Koten's reagent 132 gives up to 94% thioamino ligand 133 is reported to give up to 110% ee!147 Knochel has chosen to concentrate his asymmetric alkylzinc addition studies on the use of titanium derived complexes such as 134 as catalysts (formed in situ from the reaction between the ditriflated diamines and titanium tetraisopropoxide). Such catalysts, which are believed to be rather better than aminoalcohols for reactions of functionalised organozincs, give ee's in the region of 90-99% for the prototype reaction of Scheme 16 and related tran~formations.'~~ The Knochel system is particularly applicable to addition reactions to a,P-unsaturated aldehydes, several examples of which have been reported re~ent1y.I~~ Some impressive ee's (up to 90%) have also been obtained when 134 was used to mediate reactions of dialkylzincs with aliphatic aldehydes, a traditionally difficult process with all currently available chiral 1igands.l5' Other researchers have chosen to examine the versatility of ligand-accelerated alkylzinc addition reactions.Conditions have been found for control of the addition of diisopropylzinc to aldehydes, a hindered reagent which is normally ineffective in additions due to competing hydride transfer proce~ses.'~~ In a detailed study of mixed dialkylzincs it has been found that methyl and tert- butyl are remarkably inactive to transfer to the carbonyl compared to other alkyl groups, and therefore have potential value as non-transferable ligands in more complex In some cases the products of addition can themselves act as catalysts, thus permitting autocatalytic processes to take ~ 1 a c e .l ~ ~ This can be useful provided that all catalytic species favour formation of the same enantiomer of product. A study of the catalysed reaction of dialkylzincs with chiral aldehydes revealed that the ligand effect greatly dominates that of the chiral substrate, even when it bears an a-chiral centre.154 In terms of applications to total synthesis, perhaps the most impressive is the cyclisation of 135 to 136 in 91% de ('matched' directing effects operate) using only 1 mol% of the chiral aminoalcohol 137.15' Product 136 was taken whilst the simple on to complete an impressive synthesis of ( + )-aspicillin. Asymmetric additions of diethylzinc to C=N double bonds are rather rare.One excellent example is provided by the phosphorus protected imine 138, which gives enantiomerically enriched phosphinamides 139 (up to 85% ee) upon reaction in the presence of a polymer bound chiral amino alcoh01.l~~ Free amines may be generated from 139 upon exposure to relatively mild acid. cuprates, organozinc reagents have been employed in conjugate addition reactions to enone and related reagents.157 Together with an appropriate nickel(I1) catalyst and a suitable chiral ligand such as 140, such addition reactions have been reported to be capable of proceeding with very high ee (Scheme 17).158 An example of a related 'one-off asymmetric reaction is the combination of diethylzinc with (+)-diisopropyltartrate to give a reagent capable of promoting the asymmetric ring opening of symmetrical aziridines by thiols in up to 88% ee.'59 Whilst by no means as widely exploited as OH 138 R = Ph, 2-Np 139 R = Ph, 2-Np 1 40 Reagent: i, Ni(aca~)~, ligand 140 Scheme 17 To complete this section on zinc attention is drawn to the remarkable cyclopropanation reactions of allylic alcohols by bis(iodomethy1)zinc when used in the presence of borate esters such as 141 (Scheme 18).This methodology, first reported by Me2NOCh CONMe2 Bu 141 o p 0 R' ,++OH - .&OH R3 91-94% ee 80% yield R3 Reagent: i, 2.2 eq. Zn(CH21)2, 25 "C, CH2CI2, 2 h, ligand 141 0 135 136 (-)-DUB 137 Scheme 18 Wills: Main group organornetallies in synthesis 213Charette, has since been further developed by this author'60 and others.'61 In independent work, Denmark'62 and K~bayashil~~ have discovered that diethylzinc and diiodomethane is also an effective OEt the complex formed between protected amine 142, 1 47 148 149 material for asymmetric allylic alcohol cyclopropanation, although it is not quite as effective as the Charette method. their ability to promote cyclisation reactions onto triple'61,'65 and doublelM bonds.Spirocyclisations may be carried out using silyl enol ethers as the nucleophilic components as in the conversion of 143 to 144 after demercuration (N.B. the epimer is also formed).16% A good example of the value of this methodology is provided by the biscyclisation of 145 to 146 upon treatment with mercury(I1) triflate.'% Organomercury reagents are most remarkable for TMSO NHS02R 'NHSO~R 142 R = Me, CF3 143 144 145 146 4 Group 13 4.1 Boron In view of the marginal nature of boron as a 'metallic' compound, this section will be somewhat shorter than in previous reviews and will highlight important aspects of organoborane reactivity.4.1.1 Boron enol ethers, borane catalysts and a1 kylboranes Boron enol ethers continue to be of great synthetic significance due to their remarkable versatility and ability to introduce several stereogenic centres in one process. Their application however does require the control of two aspects; enolate geometry and diastereoselectivity of additions to aldehydes. The first has been studied in detail by Brown, who has published a series of articles on enolboration. 167 Above all, these reveal the remarkable sensitivity of the process to substrate structure and reaction conditions; treatment of 147 with dicyclohexylboron iodide and triethylamine in carbon tetrachloride gives the isomer 148 when R=Me but 149 when R=Ph.'67a In each case the selectivity in each direction is in the region of > 97: < 3.chiral boron enol ethers 150, it is perhaps the group Of those who have studied aldol reactions of of Paterson who have made the greatest use of these remarkable reagents.16' The majority of the factors controlling the selectivity of these reagents has largely now been delineated by this group, who have turned their attention to synthetic applications. Whilst a comprehensive review of the achievements of this group is not possible in an article of this type, attention is drawn to the syntheses of target molecules as diverse as ~leandomycin,'~~ swinholide been reported recently.Whilst the diisopinocampheylborane group is perhaps the most widely studied directing group, other chiral modifications of boron enol ethers may be made. For example the moderately enantioselective [2,3] Wittig rearrangement of 151 to 152 (83 : 17 in favour of this isomer) takes place via the diamine-derived enol 153.17* Menthyl-derived dichloroborane 154 has previously been shown to be a remarkable catalyst for the asymmetric Diels- Alder reaction, giving ee's of up to 99.5%! For the first time an X-ray crystal structure of a complex of this catalyst with a ketone has provided evidence to support the speculation that this stereocontrol is the result of a two point binding effect, rather than simply complexation of a lone pair on the ketone.'73 and ebelactone A and B,171 all of which have 1 50 151 1 52 fy0Me Ts Ts Ph 153 154 Alkylboranes have numerous applications in synthesis, although alkyl transfers to electrophilic reagents are not so common.One interesting recent example has been reported of such a transfer to a cyclic nitrone, a process which is promoted by initial association of a trialkylborane with the nitrone oxygen atom.'74 Chloromethylborate esters are also valuable synthetic reagents which have application in homologation reactions. The results of a detailed study of this class of reaction employing in situ generated alkyllithiums have been reported this year by 214 Contemporary Organic Synthesis4.1.2 Allyl-, allenic and alkenylboranes Allylboranes are remarkable synthetic reagents, capable of the generation of high regio- and diastereo-selectivities in addition reactions to carbonyl compounds.Asymmetric modification of these reagents renders valuable chiral reagents such as 155, a reagent which adds to acyl silanes to give products of up to 92% ee.176 These reagents may alternatively be of a complex structure, for example 156, which supplies an a-aminoallyl group in additions to aldehydes to give the product 157 with both de's and ee's in excess of 90%.'77 The related allylboronic esters 158 and 159 have probably received even further attention, Hoffman having recently examined the reactions of diol derived 158 B-Allenyl-9-BBN, a useful reagent for regio- and chemo-selective formation of homopropargylic alcohols upon reaction with aldehydes, has recently been described in a detailed publication by Brown.I8* Related vinylic boron reagents, excellent substrates for palladium catalysed coupling reactions with aryl and vinyl halides,'83 may themselves be formed by coupling reactions of boronic halides with trialkyltin alkenes.Is4 The 1,2-diborated alkene 164 is a suitable partner for cycloaddition reactions with unactivated dienes such as 165; oxidation of the primary cycloadduct then yields 1,2-trans diols 166.'@ Alkenylboranes bearing halides at the a-position react with allylic nucleophiles to give substitution products and subsequently ketones after oxidation.lg5 155 156 N Y P h Ph 1 57 158 with chiral aldehydes'78 and R o u s ~ ' ~ ~ and others180 the reactions of the tartrate derived versions 159.A versatile derivative is the menthofuran derived compound 160, which adds to aldehydes RCHO to give the trans products 161 and subsequently diols 162 upon oxidation.'79b The brominated allylic reagent 163 adds to aldehydes to give products with ee's of up to 9O%.ls0 Recently Roush has reported that improved results can in some cases be achieved using a related reagent containing an ethylene bridged tartramide in place of the ester groups in 159.18' 1 59 160 I OH 161 163 OH 162 QO; B ' 0 0 164 165 166 4.1.3 Hydroboration and carbonyl reduction by boranes Hydroboration is a pivotal transformation in boron chemistry. Few monoalkyl boranes are available to the synthetic chemist, however, the hindered thexylborane being the most widely used derivative.Another hindered compound, 2,4,6-trimethyl- phenylborane, has been reported to be a viable alternative, and benefits from relative ease of preparation and hand1ing.ls6 In terms of chiral alkylboranes, monoisopinocampheylborane 167 is well established. However minor modifications to the structure, as in the case of 168, have been reported to give reagents with dramatically improved selectivities in hydroboration reactions of representative alkenes.ls7 A potential problem with such reagents, however, is their non-availability in consistently enantiomerically pure form. To solve this problem a number of upgrading methods have been developed, one based on the formation of a 2: 1 complex with a diamine (as used to upgrade 167)'88 and the other based on the temporary formation of a trialkylb~rane.'~~ Further examples of transit ion met a1 complex mediated hydrobora t ion reactions have been reported."" 1 Y 1 167 168 169 170 R = H 1 72 171 R=Me 1 73 Wilks: Main group organometallics in synthesis 215Bis( isopinocamphey1)chloroborane 169 is an outstanding reagent for the asymmetric reduct ion ketones.Recent reports have appeared on the reductions of fluorinated ketones, which in some cases show improved or even inverted absolute asymmetric induction.'" The reagent is extremely well suited to the reduction of p-amino ketones, which may be reduced in up to 99% ee in some cases.'92 A remarkable reversal of selectivity was observed in the reduction of the closelv related of ketones 170 and 171 with 169.'93 The fbrmer gives the R-enantiomer 172 in 90% ee while the latter gives the S-enantiomer 173 in 92% ee, suggestive of an important coordination effect involving the hydroxy group.Highly selective asymmetric intramolecular reductions by chiral boranes have also been de~cribed.'~~ 4.2 Aluminium, gallium and thallium Carboalumination of terminal alkynes by trimethylaluminium may be catalysed by organozirconium complexes, the resultant vinylaluminium reagents 174 then being effective substrates for palladium catalysed coupling reactions with a-amino acetates 175 to give amino ester derivatives 176.'95 The combination of trimethylaluminium with dimethylamine gives a reagent which is highly effective for the formation of amides from esters196 whilst the use of trimethylsilyl triflate effectively activates trimethylaluminium towards gern-dimethylation of ketones.197 Although not as well established as the boron complexes described above, aluminium complexes 177 of diamines are effective catalysts of allylic acid cyclopropanation by diethylzinc and dii~domethane.'~~ Highly hindered alkoxyalkylaluminium complexes are effective Lewis acids for the promotion of several classes of transformations including hetero Diels-Alder reactions. However, most remarkable is their exquisite chemoselectivity; in certain cases straight chain aldehydes can benefit from the Lewis acid activation in the presence of more hindered derivatives due to the high level of steric hindrance around the aluminium centre.'99 In a similar way, 1,Zaddition to cyclic enones can be suppressed compared to 1,4-addition by the steric hindrance in the complex.'99 AIMe2 P h2C=NyC02R h2cT C02R H OAc R' R' 1 75 176 +H 174 H S02Ar aN\A,R BrGa/TMS BrGa-TMS " H S02Ar Gallium reagents have seen a handful of important applications.The reducing agent formed by the combination of gallium trihydride with a tertiary amine or phosphine is selective for reduction of the carbonyl group of bromoacetophenone.200 In contrast many aluminium hydride reagents would have cleaved the C-Br bond. Tetraalkylgalate complexes, formed by the reaction of an alkyllithium with a trialkylgallium, transfer a single alkyl group to acid chlorides to give ketones, a process which invariably results in formation of tertiary alcohol when other organometallics are used.201 Prop-2-ynylic and allylic organogallium compounds 178 and 179 may be prepared from the appropriate bromide precursors and react cleanly with carbonyl compounds.202 Organothallium reagents have always been somewhat underexploited in synthesis due to their toxicity.An interesting recent application of a trimethylthallium-methyllithium combination for nucleophilic additions to ketones revealed an interesting chemoselectivity; enones were considerably more reactive than the corresponding saturated compounds towards methylation, the reverse of the expected reactivity.203 5 Group4 5.1 Silicon 5.1.1 Silyl enol ethers The full range of applications of silyl enol ethers in any review period is far too vast to detail comprehensively, and therefore attention here will merely be focused on a small number of interesting studies of the stereochemistry of the reactions of these compounds with aldehydes.The great difficulty in the study of such reactions has always been in delineating all of the various effects - solvent, temperature, counterions, etc. - which contribute to a given result. Denmark has devised and studied an ingenious model based on the structure 180 which reduces the problem to that of an intramolecular reaction within a very well defined steric framework. The results of cyclisation studies of 180 have painted a complex picture however: there appears to be an inherent modest preference for an open, anti-periplanar reaction 1 80 HO 181 0 OH M e O v P h Me Me 182 177 178 179 1 83 216 Contemporary Organic Synthesismode (to give 181) in the presence of a range of Lewis acids and fluoride sources.2o4 In other cases the selectivity can be reversed, suggesting a chelation between the reaction partners. Denmark has also reported recently on the use of silacyclobutane derived enol ethers 182, which give predominantly (93 : 7-99 : 1) the syn aldol products 183 upon reaction with aldehydes.205 The incorporation of a chiral alkoxy group on silicon also results in asymmetric inductions of up to 97% in the case of ( - )-tralzs-2-cumylcyclohexanol.205 5.1.2 Allyl-, benzy- and alkenylsilanes and their derivatives Allylsilanes 184 may be made efficiently by the palladium catalysed reduction of allylic acetates 185 by sodium formate; regioselective hydride transfer to the terminal position of the intermediate complex is observed.206 Another method which allows full control of regio- and stereo-selectivity is the nickel catalysed coupling reaction of vinylselenides with a-trimethylsilylmethyl Grignard reagent^.^" In a series of systematic studies on a stereochemically well-defined substrate 186, which follow on from previous work, Denmark has examined the intramolecular Lewis acid catalysed cyclisations of allylsilanes and stannanes with aldehydes2'* These studies suggest that an anti electrophilic substitution process operates, i.e.the trialkylsilyl group is anti to the face of the ally1 group which reacts with the aldehyde. f CHo R S i P h M e , D TMS RFTMS R- OAc 184 185 186 Unlike allylboranes, allylsilanes generally require assistance from a Lewis acid to react with aldehydes.Allylsilacyclobutanes 187 appear to be rather more reactive than average and undergo non-catalysed additions at 130 O C . * 0 9 A rare example of Lewis base catalysed addition of allyltrichlorosilane to aldehydes has also been reported; phosphinamides act as the Lewis bases of choice in this This process also benefits from the fact that a homochiral phosphinamide may be employed to induce asymmetry in the reaction. In practice 188 was found to be the best reagent: 1 equivalent of 188 gave an ee of 63% for the reaction shown in Scheme 19. It is noteworthy that the two studies 187 1 88 i Ph c,3siN + PhCHO - Reagent: i, 1 eq. 188, -78 "C, CH2CI2 63% ee Scheme 19 above also came from Denmark's laboratory, which underlines his very important contributions to this area.In contrast to aldehydes, oxonium cations react rapidly with allylsilanes, a process which can be used to advantage in intramolecular cyclisation reactions.21 In the acid catalysed reaction between 189 and acetal 190, the intermediate 191 cyclised via the corresponding oxonium cation to give 192 with a high degree of diastereocontrol.212 Addition reactions, in the presence of a suitable Lewis acid, of allylsilanes to carbon-nitrogen double bonds have been rep~rted.~'" A related intramolecular cyclisation process featured an allylsilane cyclisation onto the cationic intermediate in a Beckmann Epoxide opening reactions can promote intramolecular allylsilane-terminated processes, an excellent example of which is the conversion of 193 to 194 upon activation by dichloromethylaluminium at -78 0C.215 The silyl group is essential for the success of this transformation. Rl+o"2 OR2 OH 190 MeSSi 189 R 2 0 q 0 'R II 191 1 92 193 In some cases Lewis acid catalysed allylsilane additions to electrophiles can give rearrangement products.The use of niobium pentachloride, for example, results in the formation of a product containing a cyclopropane ring.216 Reactions with Wills: Main group organornetallies in synthesis 217alkynes bearing electron withdrawing groups may give products of overall [3 + 21-cy~loaddition.~~~ Scheme 20 features a remarkable example in which two sequential reactions of this type take place.217a A similar process can on occasions take place in additions to ketones;218 however in some cases [2 + 21-cycloaddition reactions can compete.219 Reagent: i, TiC14, CH2CI2.-78-20 "C Scheme 20 Palladium(0) complexes can assist the reactions of allylsilanes with allylic acetates220 and aryl triflates.221 The incorporation of a chiral diphosphine can render this process asymmetric. An example is the formation of 195 in 91% yield and 92% ee from 196 when R-BINAP is employed as the ligand in the catalyst.222 Coupling of allylsilanes with benzylsilanes may be achieved by oxidative HO HO I L S i M e 3 \\ 195 1 96 Pr0p-2-ynylic~~~ and allenic ~ i l a n e s ~ ~ ~ may participate in intramolecular cyclisation reactions. The reaction of 197 with benzylamine in the presence of tin tetrachloride gives 198 with a high degree of stereocontrol via cycloaddition onto the intermediate imine.225 Compound 198 is an advanced intermediate in the synthesis of the C2 symmetric compound papuamine.An alkynylsilane, 199, is an advanced intermediate employed in the key step of the synthesis of a cyclic enediyne compound 200; dry caesium fluoride is employed to promote the reaction.226 H 1 97 R 198 A silicon atom has been used as part of a temporary 'tether' to mediate the intramolecular [2 + 21-cycloaddition between an alkenylsilyl group and the carbon-carbon double bond of an enone. Following the reaction the silicon was removed in an oxidative process to give a d i 0 1 . ~ ~ ~ Stereoselective epoxidation of an allylsilyane followed by a concerted intramolecular cyclisation, silyl migration and epoxide opening provided a means for the stereoselective formation of y-lactones, precursors of building blocks for nonactin.228 5.1.3 Other classes of silicon reagent Trialkylsilanes are ubiquitous reagents for the protection of alcohols.Whilst it is not possible to present a comprehensive review, the ability to selectively remove a tert-butyldimethylsilyl group from either an aliphatic or phenolic position, depending on the exact conditions used, is noteworthy . 229 double bonds may be employed to promote intramolecular cyclisations of 1,5-dienes, provided an ytterbium catalyst is Intramolecular asymmetric hydrosilylation of 201, using a combination of rhodium(1) with S-BINAP gives the siloxacycle 202 in up to 96% ee.231 Rhodium catalysed hydrosilylation of N-acyl enamines results in introduction of the silyl group a- to the nitrogen atom, as in 203.232 Asymmetric ketone hydrosilylation may also be achieved by the use of appropriate complexes of rhodium ( I ) ~ ~ ~ and a similar asymmetric reduction process of nitrones by the use of a ruthenium-BINAP combination (ee's up to 91%).234 This hydrosilylation process can also be used to prepare silanes which are chiralat silicon; reaction of 1-naphthylphenylsilane with symmetrical ketones, catalysed by a rhodium(1) BINAP catalyst, is reported to give products 204 of up to 99% ee. Subsequent reaction of 204 with methylmagnesium bromide results in conversion to the corresponding chiral silane 205 in equally high ee.235 The insertion reaction of carbenes into silicon-hydrogen bonds has been shown to be an effective method for the preparation of alkylsilanes.236 Hydrosilylation reactions of carbon-carbon R A 0 - p H 201 199 200 R 204 0 H- R P - 202 Yh Si Me I-Np' 1 "H 205 R' 203 PhMe2Si-Li 206 218 Contemporary Organic SynthesisAcylsilanes may be prepared by the ring opening of silylated epoxides, followed by oxidation of the a-hydroxy silane product.237 The addition of carbanionic nucleophiles to chiral acylsilanes can in some cases be a diastereoselective although in some cases a synthetically useful silyl migration from carbon to oxygen takes place.239 Lithiated silanes 206 may be formed from the and participate in stereocontrolled conjugate addition reactions to chiral electrophiles such as 207.24’ Oxidation of the intermediate adduct 208 gives the enantiomerically enriched P-hydroxy product 209.Ph 207 208 209 5.2 Germanium The germanium equivalent of the Peterson reaction has been known for some time. Recently however the X-ray crystal structure of the ketone addition intermediate has been solved.242 Ally1 germanium reagents, formed in situ from ally1 bromides, react efficiently with aldehydes via the tetra-coordinated intermediate 210.243 Alkenylgermaniums have been prepared from terminal alkynyl~ilanes.’~~ 21 0 5.3 Tin Asymmetric aldol reactions may be mediated by the combination of a tin(ii) complex with an appropriate chiral diamine, a process which has now been refined for a wide range of asymmetric addition of tributyltin to aldehydes may be catalysed by chiral quaternary amine salts, although in rather modest ee (up to 24%).246 The intramolecular cyclisation of a vinyl iodide with an aldehyde may be mediated by tributyltin anion generated in situ by the reaction between trimethylsilyltributyl tin and caesium (generated in situ from the bromides) with aldehydes may be catalysed effectively by copper( I) In most cases, however, allyltin compounds may be prepared by a variety of methods, and isolated before use. The most common application of allyltins is in reactions with aldehydes, in which high stereoselectivities are invariably achieved.In some cases palladium salts provide a conveniently mild form of catalysis.249 Studies of the The The Barbier coupling reaction of allyltins functionalised reagents 211250 and 212251 have been reported.Remote functional groups can have a dramatic stereodirecting effect,252 an example of which is 1,7-asymrnetric induction in the addition reaction of 213 to aldehydes RCHO, upon SnBu3 & R 4 q S n M e 3 R2 OBn 21 1 21 2 B u 3 S n v OH OH 21 3 21 4 21 5 21 6 21 7 treatment with tin tetrabromide, to give 214 in high de.252” In this reaction the tin tetrabromide exchanges with the organometallic to give a terminal alkene which then adds to the aldehyde via a chelated transition state 215. A similar chelating effect operates in a very attractive example of an ally la t ion of an unprotected a- hydroxy ketone. 253 a-Alkoxyallylstannanes such as 216 can be prepared by the insertion of carbenes into tin- hydrogen of acyltin reagent^."^ The reactions of these compounds with aldehydes to give products 217 are highly selective, although rearrangement to y-alkoxyallyltin compounds 218 usually precedes the addition reaction.In the case of 216 indium trichloride catalysis was employed to give products with ee’s in excess of 95%.256 Full details of the additions of this class of reagent to numerous classes of aldehyde have been reported by Allyltin reagents such as 218 may be made by the SN2’ reaction of cuprates with vinyltin reagents such as 219.258 A word of caution regarding the catalysis of the addition reactions - the use of a fluoride source along with boron trifluoride has been reported to effect conversion of the enol ether unit of 218 to the corresponding aldehyde, an unexpected An asymmetric version, containing a carbohydrate derived directing group, has been reported by Roush.260 Intramolecular reactions of allyltin reagents onto aldehydes26’ and oxonium cations,262 have been or by the asymmetric reduction Me3uM0M Me B u 3 s n ~ o E t OEt 21 8 21 9 Wills: Main group organornetallies in synthesis 219reported. Typical is the stereoselective conversion of bromide 220 to 221 upon reaction with excess activated tin(0).261" Allyltin compounds also react with alkyl iodides (a radical process)263 and in cycloaddition reactions with singlet oxygen.264 Allenyltin compounds 222 undergo stereoselective additions to aldehydes, the selectivity of which depends on the method of catalysis; using boron trifluoride, 223 is formed whilst the isomer 224 results from the same reaction in the presence of tin tetrachloride.265 220 221 222 223 224 a-Alkoxymethyltin derivatives 225 may be prepared by a number of methods, and in enantiomerically pure form by the reduction of acyltin compounds or the corresponding acetals.266 Oxidation of these reagents by ozone provides a means for the synthesis of most synthetically powerful when used as a-alkoxymethyl anion equivalents, a process which can in some cases be assisted by palladium(0) catalysis.26s Such compounds also participate in intramolecular cyclisation reactions onto bromonium cations269 and couple to allyltrimethylsilanes under anodic oxidation conditions.270 Transmetallation of trialkyltin substituted epoxides has been reported,271 as have a series of studies on the 2-trialkyltin substituted tetrahydrofurans 226.272 A synthesis of a-aminotributyltin compounds 227 has been although they are SnBu3 RR'N-( OR1 R RASnBu3 R2 225 226 227 RIX RYiMe3 SnMe3 R2 Ill XR' 228 X = 0, S; R', R2 = alkyl 229 X = 0, S; R1, R2 = alkyl \SnBu3 230 231 reagent.276 Another versatile approach to the synthesis of trans-vinylstannanes, in this case from aldehydes, has been described by Hodgson (Scheme 2 1) .277 + Bu3SnCHBr2 i * R4SnBu3 H Reagent: i, 4 eq.CrCI2, LII, DMF, THF, 25 "C Scheme 21 Vinylstannanes are most commody employed in palladium catalysed coupling reactions with a range of reaction partners including acid aryl halides279 or each other.280 In the field of natural product synthesis cis-1,2-bis(trimethyltin) 232 is an excellent reagent for the late-stage formation of enediyne units in the synthesis of the dynemicin antitumour antibiotics.281 In a synthesis by Danishefsky the two alkynyl iodides in 233 were connected, to give 234, using this reagent.In his synthesis of strychnine, Overman employed a palladium catalysed carboarylation reaction between a vinyltin, an aromatic iodide and carbon monoxide as a key step.282 232 Although vinyltin reagents may be prepared from alkynes using palladium catalysed additions of various tin sources,274 the regiochemistry of this process can often be difficult to One example of a regioselective reaction, however, is the exclusive formation of the useful building block 228 from 229.275a The preceding example was reported by the Kocienski group, who have also described a regio- and stereo-selective formation of vinylstannane 230 by treatment of the lithiated I dihydrofuran 231 with a tributylstannane cuprate 233 OMe 234 220 Contemporary Organic Synthesis6 Group 15 6.1 Phosphorus The area of ligands which are chiral at phosphorus has been reviewed recently.28' The protection of phosphines with borane, which may then simply be removed by treatment with excess amine, is an idea which has received increased attention recently.284 Such ligands, for example 235, may be prepared directly by the reaction of borane-coordinated phosphorus anions 236 with appropriate electrophiles, in this case 237.284" Knochel has described the preparation of functionalised phosphines via the reaction between functionalised organozincs and chloropho~phines.~~~ Once again the borane-protected phsophines are actually isolated./ PhSe, ,, 235 236 237 6.2 Arsenic, antimony and bismuth Together with a palladium source, salts of all three of the metals in this section have been shown to be capable of catalysis of the conjugate addition reaction of sodium tetraphenylborate with enones.286 Arsenic ylides have been employed for the synthesis of a-phenylselenyl acrylatesZR7 and for the synthesis of 3-hydroxy leukotrienes from lactol precursors.288 In the latter case, the olefination reaction proceeded with a high degree of trans-selectivity. sources of aryl groups in conjugate addition reactions to en one^^^^ or in carboxylation reactions2w in the presence of an appropriate palladium catalyst. Allenylantimony reagents have been used in addition reactions to aldehydes.291 Triaryldibromobismut h compounds have been used effectively as reagents for the dehydration of secondary and tertiary alcohols.292 Bismuth ylides give epoxides upon reaction with aldehyde^.^^' Triarylbismuth reagents can be activated towards N- arylation of cyclic a m i n e ~ .~ ~ ~ Triarylantimony reagents may be employed as 238 239 I Boc Boc 240 241 1 -p henylselenyl-2-trime t hylsilylet hene with enones gives a cyclopropane as the product via a selenium assisted 1,241~1 shift.299 Homochiral selenium reagents can give enantiomerically enriched alkene addition produ~ts.'~ The reaction of styrene with 242 results in the formation of 243 and subsequently 244 in 98% ee after reductive cleavage of the carbon- selenium bond."& A similar directing group was employed for the synthesis of ally1 amines from chiral selenium compounds in ee's of 77 to 87%.'"' I 242 PhAOMe 244 243 Alkylselenium reagents may be employed in radical reactions; several recent examples of intramolecular cyclisations onto double and triple bonds have been reported.These reactions may be terminated by tributyltin h~dride,~'~ resulting in a reductive cyclisation, or by the alkylselenyl radical, to give the product of addition across the unsaturated bond.'03 In the case of enol ethers the radical addition invariably takes place at the P-position (hence the alkylselenium is incorporated adjacent to the alkoxy and good diastereoselectivity may be obtained if the substrate is ~ h i r a l .~ ' ~ The radical generated from sulfoxide 245 may be trapped with allyltin compounds to give 246 as a mixture of isomers.306 A Pauson-Khand 7.1 Selenium &SePh ?- Ci"; 7 Group 16 0- 0- Phenylselenium halides are excellent reagents for the promotion of intramolecular cyclisation 245 246 247 reactions.295 A 6-exo-trig cyclisation of O-ally1 oximes provides an efficient entry to the quinolizidine J& If' o&H alkaloids;296 however most of the reported as in the representative conversions of oxime 238 to 239297 and tryptophan derivative 240 to 241.298 The H SePh tin tetrachloride catalysed reaction of trans- 248 249 250 R2SiH cyclisations proceed through the 5-endo m ~ d e , ~ ~ ~ . ~ ~ ~ 0 --OH H-- Wills: Main group organometallics in synthesis 221reaction followed by a radical cyclisation transforms 247 into tricyclic product 248 in two steps - a powerful reaction c~mbination.~’~ A sequence involving radical addition across a triple bond, hydride abstraction from silicon and further cyclisation converts 249 into the silacycle product 250 in one remarkable by the oxidative reaction of an alkylselenyl- aluminium complex with aldehydes,m also participate in radical cyclisation reactions.310 An outstanding example is the conversion of 251 to the tetracycle 252 (a 1 : 1 mixture, 53%) in one step with a combination of tributyltin hydride and AIBN.310” Acylselenium compounds, which may be prepared COSePh 251 252 The preparation and use of selenoglycosides as reagents for the synthesis of polysaccharides has been described in some detail.These reagents provide an excellent balance between stability and reactivity and are excellent synthetic reagents.”’ Intramolecular cyclisations onto a-seleno carbenium ions formed from selenium-oxygen heteroacetals have been described.312 7.2 Tellurium Sodium hydrogen telluride, and close derivatives thereof, are powerful reducing agents for double and triple bonds313 and are particularly efficient at the conversion of epoxides such as 253 into the corresponding allylic alcohols 254.314 Other leaving groups may be used in place of tosylate in this sequence which permits the asymmetric synthesis of allylic alcohols from readily available Sharpless epoxidation products. 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