Tricarbonyliron complexes an approach to acyclic stereocontrol Liam R Cox*,a and Steven V. Leyb a Laboratorium für Organische Chemie ETH-Zentrum Universitätstrasse 16 CH-8092 Zürich Switzerland b Department of Chemistry University of Cambridge Lensfield Road Cambridge UK CB2 1EW p-Allyltricarbonyliron lactone complexes h4-dienetricarbonyliron complexes and their relatives offer an interesting approach to the problem of acyclic stereocontrol. Functional groups appended to the organic ligand frequently adopt a preferred conformation. This combined with the steric bulk of the Fe(CO)3 moiety provides a means for controlling the addition of reagents to such pendant functionality in a defined manner. Thus addition of nucleophiles to aldehydes and ketones affords a route to diastereoisomerically pure secondary and tertiary alcohols while olefinic functionality in the side-chain can be utilised in stereoselective dihydroxylations Diels–Alder and Michael addition reactions.Just as the formation of arene Cr(CO)3 complexes modifies reactivity at the a-position of arene substituents the Fe(CO)3 group of h4-diene and trimethylenemethane tricarbonyliron complexes can be used to stabilise an adjacent positive charge. Trapping of the carbocation resulting from ionisation of an a-carbinol occurs with high diastereoselectivity providing an unusual and useful stereoselective SN1-type reaction. Such highly stereoselective reactions have been put to good use in the preparation of a number of biologically interesting natural products.1 General introduction The last few decades have seen an explosion of new methodology for organic synthesis. This has been fuelled by the need to perform reactions with increasingly high levels of chemo- regio- and stereo-control. As synthetic targets have become more complex this demand for high specificity and control has resulted in chemists reaching to all regions of the periodic table to develop reagents not only for modifying and Liam R. Cox graduated from the University of Cambridge in 1994 with BA (hons) in Natural Sciences. He remained in Cambridge for his PhD working with Steve Ley on the chemistry of p-allyltricarbonyliron lactone complexes. He is currently carrying out postdoctoral studies with Professor Dr François Diederich at the ETH in Z�urich.Steven V. Ley Steven V. Ley is currently the B.P. 1702 Professor of Organic Chemistry at the University of Cambridge. He studied for his PhD at Loughborough University working with Harry Heaney and carried out postdoctoral work in the United States with Leo Paquette at The Ohio State University and then with Derek Barton at Imperial College. He remained at Imperial College Liam R. Cox O Fe(CO)3 O O BF3 H Me C5H11 Me H Sn improving existing transformations but also for making new processes possible. The development of organometallic reagents derived from transition metals has been particularly successful and has had a profound effect on synthetic planning and design.Iron is clearly an important and synthetically useful transition metal. Its high natural abundance and ready accessibility have resulted in the development of a wide and varied organometallic chemistry. Most low valent organoiron complexes derive from inexpensive ironpentacarbonyl [Fe(CO)5] or from one of its higher order congeners diironnonacarbonyl [Fe2(CO)9] and triirondodecacarbonyl [Fe3(CO)12]. Such iron carbonyl complexes are relatively easy to prepare and can generally be handled without the need for specialised techniques or apparatus. Complexes can be formed with a wide range of organic substrates. These are usually sufficiently stable to survive a variety of functional group manipulations on side-chain appendages yet can be easily decomplexed when required.1,2 A number of different types of organometallic complexes bearing the tricarbonyliron [Fe(CO)3] moiety have been reported.Treatment of vinyl epoxides or vinyl cyclic sulfites with Fe(CO)5 or Fe2(CO)9 affords p-allyltricarbonyliron lactone complexes 1,3 while dienes capable of adopting an s-cis conformation react to form h4-dienetricarbonyliron complexes 2.1,4 Suitably functionalised h4-diene complexes in turn can be used to generate h5-pentadienyltricarbonyliron cationic (+1) complexes 3. 1,3-Dibromo- or dihydroxy-alk-2-enes have also been found to react with iron pentacarbonyl affording trimethylenemethane (TMM) tricarbonyliron complexes 4 (Fig. 1). This review is concerned with the use of the tricarbonyliron moiety as a temporary structural feature to control the until 1992 when he moved to Cambridge to take up his present position.He has been the recepient of numerous awards including the Royal Society of Chemistry Organic Synthesis Award the Natural Products Award the Simonson Pedler and Rh�one Poulenc lectureships the Flintoff Medal and the Adolf Windaus Medal. Most recently he was awarded the prestigious Paul Janssen Prize for Creativity in Organic Synthesis and the Bakerian Lectureship of the Royal Society. He is engaged in research covering a diverse range of areas including total synthesis of complex natural products new synthetic methodology organoiron chemistry combinatorial chemistry solid support chemistry and the assembly of large oligosaccharides.301 Chemical Society Reviews 1998 volume 27 O O Fe(CO)3 O Fe2(CO)9 –O O S p-allyltricarbonyliron lactone complex 1 O Fe(CO)3 Fe(CO)5 Fe(CO)3 Fe(CO) h4-dienetricarbonyliron complex 2 3 HBF4 BF4 – OH h5-pentadienyltricarbonyliron (+1) cationic complex 3 Fe(CO)5 X Fe(CO)3 X = Br OH trimethylenemethane tricarbonyliron complex 4 Fig. 1 A variety of tricarbonyliron complexes are readily prepared stereochemical outcome of reactions carried out on functional groups appended to the organic ligand. Such a strategy can be used to effect stereocontrolled reactions on acyclic systems a challenging problem which remains at the forefront of organic synthesis. While this is not intended to be an exhaustive review of the chemistry of tricarbonyliron complexes,1–5 the areas chosen for discussion are representative of what can be achieved using this methodology.Thus by highlighting the concepts behind this approach to acyclic stereocontrol in addition to its scope and limitations it is hoped to provide a platform from which further imaginative and novel uses of these complexes in modern synthetic design may be conceived. 2 Tricarbonyliron complexes exhibit planar chirality Dienes have been the most intensively studied organic substrates for complexation with the tricarbonyliron group. Reaction with any unsymmetrically substituted diene affords a racemic product by virtue of the iron moiety being able to complex to either of the prochiral faces of the diene substrate; the resulting complex possesses planar chirality (Fig.2). Fe(CO)3 Fe(CO)3 X Fe(CO)5 Fig. 2 Prochiral diene substrates afford a racemic complex Efficient procedures have been developed which permit access to enantiomerically enriched complexes frequently by applying classical resolution techniques on the racemate.1 Enantiomerically enriched h4-diene complexes can alternatively be prepared by decarboxylation of enantiomerically enriched Chemical Society Reviews 1998 volume 27 302 p-allyltricarbonyliron lactone complexes (vide infra).3,6 Trimethylenemethane tricarbonyliron complexes and h5-pentadienyltricarbonyliron (+1) cationic complexes also possess planar chirality and may be prepared in enantiomerically enriched form by similar methods.The vinyl epoxide or cyclic sulfite precursors for p-allytricarbonyliron lactone complexes are themselves chiral molecules which are readily prepared in enantiomerically enriched form using Sharpless Asymmetric Epoxidation and Dihydroxylation protocols.7,8 The mechanism of complex formation ensures that the enantiomeric excess in the organic precursor is preserved in the product complex. p-Allyltricarbonyliron lactone complexes are therefore also readily obtained in enantiomerically enricherm.3 3 A model for the use of tricarbonyliron complexes as stereocontrolling agents Since the majority of methods for complex formation are mild a wide range of functionality can be incorporated into sidechains of the organic ligand.It was postulated that the inherent chirality of these complexes could be utilised to perform asymmetric transformations of functional groups attached at the periphery of the organic ligand. Specifically the steric encumbrance provided by the Fe(CO)3 moiety could enforce a degree of facial selectivity on reactions carried out on planar functional groups (e.g. carbonyl groups and double bonds) held in close proximity to the ligand by blocking one of their diastereotopic faces. This would also rely on the functional groups themselves occupying a preferred conformation in which the two faces are in different steric environments (Fig. 3). bulky Fe(CO)3 group blocks top face CO CO CO Fe FG ligand reagent functional group preferentially adopts a single conformation reagent attacks from the exo face Fig.3 Model for asymmetric synthesis using tricarbonyliron complexes Examples in which tricarbonyliron complexes have realised their potential for use in the construction of new stereogenic centres will be discussed in the following sections. 4 Nucleophilic addition to carbonyl groups in the side-chain of the organic ligand. The addition of nucleophiles into carbonyl groups is a reaction of fundamental importance and remains one of the most widely used transformations in synthesis. Under normal circumstances the nucleophilic reagent adds indiscriminately to either face of the prochiral carbonyl group affording a racemic mixture of products.Differentiation of the two enantiotopic faces can be achieved by steric blocking allowing the preparation of enantiomerically enriched products by ensuring the two different addition pathways are different in energy. If the reaction is under kinetic control then the larger the difference in activation energies the greater the enantiomeric excess of the addition product. Two criteria must be satisfied if the addition of a nucleophile into carbonyl functionality appended to the organic ligand of a tricarbonyliron complex is to proceed with high diastereocontrol. First the carbonyl group must adopt a single reactive conformation. Second its two diastereotopic faces should be sterically differentiated by the tricarbonyliron moiety such that addition proceeds ideally to exclusively the less hindered face.Non-complexed dienones normally exhibit multiple bands in the carbonyl stretching region of their IR spectra owing to the presence of s-cis and s-trans conformations both of which are significantly populated at ambient temperatures. Upon complexation to Fe(CO)3 however a single CNO stretching frequency is observed suggesting that only one conformer is significantly populated.9 The preference of ketone-functionalised dienetricarbonyliron complexes to adopt a single conformation is widely accepted and both NOE and X-ray data support the exclusive adoption of an s-cis conformation. Similarly p-allyltricarbonyliron lactone complexes bearing ketone functionality in the side-chain of the allyl ligand adopt exclusively an s-cis conformation in both the solid state (as determined by X-ray structure analysis) (Fig.4) and importantly also in solution (as determined by NOE NMR studies) (Fig. 5).10 Fig. 4 X-Ray structure of complex 5 reveals that ketone functionality in the side-chain adopts an s-cis conformation O O Fe(CO) no NOE observed 3 Fe(CO)3 O O H H O H O H 6 20.3% Fig. 5 NOE data showing that ketone functionality in the side-chain of lactone complex 6 adopts an s-cis conformation in solution Residual conjugation to the organic ligand would be expected to favour the adoption of s-cis and s-trans conformations (as opposed to non-coplanar conformations). Furthermore analysis of steric interactions between the alkyl substituent on the ketone and the ligand reveal the s-trans conformation to be disfavoured (Fig.6). The adoption of the s-cis conformation by a ketone group is presumably a result of minimisation of these steric interactions but may also be owing at least in part to electrostatic effects i.e. the minimisation of unfavourable dipole–dipole interactions. Fe(CO)3 (CO)3Fe H O R H R H O s- trans s- cis A1,3-strain destabilises s- trans conformation Fig. 6 The s-cis conformation is preferentially adopted by ketone functionality in side-chain appendages of tricarbonyliron complexes The first criterion for diastereofacial selection appears to be satisfied; ketone groups adopt exclusively an s-cis conformation. Furthermore the X-ray crystal structures of ketone complexes such as 5 suggest that the blocking capability of the tricarbonyliron unit is high with one of the carbonyl groups being positioned directly over and therefore preventing direct access to one of the stereofaces of the ketone group (Fig.4). On the basis of structural analysis of both h4-diene complexes and p-allyltricarbonyliron lactone complexes a model predicting the stereochemical outcome of the addition of a nucleophile into a ketone group appended to the organic ligand can be proposed (Fig. 7) the approaching nucleophile should attack anti to the tricarbonyliron moiety producing an alcohol stereogenic centre of predictable configuration. CO O CO Fe O CO O R Nu– CO O CO Fe O CO OH Nu R alcohol stereogenic centre with predictable configuration Fig.7 Model used to predict the stereochemical outcome of addition of nucleophiles to ketone groups in the side-chain of tricarbonyliron complexes Aldehydes might be expected to be less conformationally restricted owing to diminished steric interactions between the aldehydic hydrogen and the organic ligand. This would allow relatively free rotation about the C–CNO bond and significant population of both s-cis and s-trans conformations. NOE studies corroborate this hypothesis.11 Irradiation of both the aand b-hydrogens of the allyl ligand of lactone complex 7 reveal NOEs to the aldehydic proton resonance suggesting that in chloroform solution both s-cis and s-trans conformations are populated (Fig.8). Thus from conformational analysis of carbonyl-functionalised Fe(CO)3 complexes one would anticipate that nucleo- Chemical Society Reviews 1998 volume 27 303 O O Fe(CO)3 Fe(CO)3 H O 10.1% O O H H H O 7 4 3 4.7% Fig. 8 NOE studies show that aldehyde functionality in the side-chain of lactone complex 7 adopts both s-cis and s-trans conformations philic addition to ketone groups would be highly diastereoselective with a predictable stereochemical outcome. The diastereoselectivity in additions to aldehydes would be expected to be lower and the stereochemical outcome less easy to predict. This has for the most part turned out to be the case. 4.1 Nucleophilic addition to ketone functionality in the side-chain of tricarbonyliron complexes The reduction of dienone tricarbonyliron complexes by NaBH has long since been shown to be highly diastereoselective.9 Franck-Neumann et al.have further shown that 1-keto h4-diene complexes 8 react with complete stereocontrol with organolithium reagents affording a single diastereoisomeric product 9. The stereoselectivity is readily accounted for by the proposed model with addition of the nucleophile proceeding onto the s-cis-conformation of the ketone anti to the bulky Fe(CO) group (Scheme 1).12 Fe(CO)3 Fe(CO)3 O R¢Li OH R' R R 9 8 R = Me Et cyclohexyl R¢ = Ph Et Me Scheme 1 Organolithium nucleophiles add in a highly stereoselective fashion to ketone functionality in the side-chain of h4-diene complexes Reduction of ketone groups appended to the allyl ligand of p-allyltricarbonyliron lactone complexes is best achieved using organoaluminium reagents bearing sterically bulky alkyl groups.10 In these cases b-hydride transfer is a more facile process than whole group transfer and the resulting secondary alcohol product is obtained exclusively as a single diastereoisomer in complete accord with the proposed model.Such a stereoselective reduction of ketone functionality in the sidechain of a lactone complex was a key step in the synthesis of b-dimorphecolic acid 10 (Scheme 2).13 Treatment of functionalised lactone complexes 11 and 12 with Bui 3Al afforded the secondary alcohols 13 and 14 as single diastereoisomers in 72% combined yield.After chromatographic separation the next key step involved a stereoselective base induced decarboxylation of 13 to the corresponding (E,E)-h4-diene complex 15.6 Subsequent manipulations led to the first total synthesis of b-dimorphecolic acid 10. Unlike their diene complex relatives p-allyltricarbonyliron lactone complexes are unstable to strongly Lewis basic nucleophiles such as Grignard and organolithium reagents. However more Lewis acidic nucleophiles such as organoaluminium reagents and allylstannanes (in the presence of a Lewis acid) react chemoselectively with carbonyl functionality in the side-chain of the organic ligand leaving the complex itself intact. These nucleophiles react with ketone groups in the sidechain of the allyl ligand to afford the corresponding tertiary alcohol products with excellent levels of stereocontrol (Scheme 3).10,14 In all cases only one diastereoisomer could be observed by either NMR spectroscopic or HPLC analysis.The excellent levels of stereocontrol and the relative configuration of the newly generated stereogenic centre are entirely consistent with Chemical Society Reviews 1998 volume 27 304 O O C5H11 (CH2)8OTBDPS Fe2(CO)9 THF 64% O Fe(CO)3 O O TBDPSO(CH (CH2)8OTBDPS C5H11 3:1 11 Bui 3Al 72% O Fe(CO)3 O OH (CH TBDPSO(CH2)8 C5H11 3:1 13 2)8OTBDPS Ba(OH)2 78% OH C5H11 (CH2)8OTBDPS 15 Fe(CO)3 steps OH C5H11 O 10 3 O (CH2)7CO2H Scheme 2 SnBu3 O BF3•OEt2 0 °C 5 O Fe(CO) Fe(CO) 3 O O Me3Al 0 °C Scheme 3 Allylstannanes and organoaluminium reagents react in a highly diastereoselective fashion with ketone functionality in the side-chain of lactone complexes the proposed model (Fig.7) the nucleophile approaches anti to the bulky tricarbonyliron moiety and reacts with the s-cisconformation of the ketone. Reaction of ketone complex 16 with crotyltributylstannane generates only two products 17 and 18 out of the four possible diastereoisomers.14 Thus while the Fe(CO)3 unit exerts absolute 92 % de >95% O (OC)3Fe O O 2)8 C5H11 12 O (OC)3Fe O HO C5H11 O Fe(CO) 14 3 O OH O Fe(CO) 90 % de >95% 3 O OH control over the formation of the tertiary alcohol centre it fails to control the stereochemical outcome of the adjacent centre.This is consistent with the reaction of ketones with crotyl metal reagents the difference in effective size of the groups either side of the carbonyl group is small allowing the reaction to proceed equally well through two possible open transition states (Fig. 9). O O 3 O O O BF3 H H Me C5H11 Fe(CO) 16 Me Sn O H 3 O OH C H Fe(CO) 5H11 H 17 Fig. 9 Reaction of ketone complex 16 with crotyltributylstannane affords two diastereoisomeric complexes 4.1.1 Conclusions Addition of nucleophiles into ketone-functionalised tricarbonyliron complexes occurs with complete stereocontrol.The reaction provides a method for generating tertiary alcohol products of known configuration. This is a particularly valuable process as other methods for generating this type of stereogenic centre are rare. The excellent levels of stereocontrol can be attributed to the ketone adopting exclusively the s-cis conformation and addition proceeding anti to the bulky Fe(CO)3 group. In the case of p-allyltricarbonyliron lactone complexes the reaction may be considered as a novel example of remote induction of chirality since there is a 1,5 relationship between the lactone tether and the newly formed tertiary alcohol stereogenic centre. H Fe(CO)3 MeO2C 19 1 MeLi 2 nucleophile (RM) CH2 MeMgI Me3Si • 3 C5H11 Scheme 4 Diastereoselective addition of nucleophiles into aldehyde functionality appended to h4-diene complex 19 / TiCl4 O BF3 Me C5H11 Fe(CO)3 Me Sn O Fe(CO)3 O OH C5H11 H H MeO2C 18 RM O H RM adds to s- cisconformation of the aldehyde combined yield (%) 4.2 Nucleophilic addition to aldehyde functionality in the side-chain of tricarbonyliron complexes 4.2.1 Nucleophilic addition to aldehyde functionality in the side-chain of h4-dienetricarbonyliron complexes Owing to their ease of preparation the addition of nucleophiles to aldehydes attached to h4-dienetricarbonyliron complexes has received the most attention.Synthesis of h4-diene complexes bearing aldehyde functionality in the side-chain was first reported by Stone and co-workers in 1961.15 A number of different nucleophiles have since been reacted with aldehyde 19 and some of the results are summarised in Scheme 4.By convention addition to the s-cis-conformation of the aldehyde leads to the Yexo derivative 20 while addition to the s-trans conformer gives the Yendo product 21.9 Strongly Lewis basic nucleophiles such as organolithium and organomagnesium reagents react preferentially with the s-cis-conformation of the aldehyde adding anti to the Fe(CO)3 group and generating the Yexo isomer as the major product.5 Organolithiums are normally more diastereoselective than Grignard reagents but overall levels of diastereoselectivity remain only moderate. Lewis acidmediated nucleophilic additions generally give the Yendo product as the major isomer,5,16 sometimes exclusively (see entry 3 of table Scheme 4).17 No other general patterns are apparent the diastereoselectivity of the reactions is highly dependent on a number of features including temperature nature of active nucleophile and the presence or absence of a Lewis acid.All these variables will potentially affect the relative populations of s-cis and s-trans aldehyde conformers and hence the diastereoselectivity assuming that addition proceeds exclusively to the face anti to the bulky Fe(CO)3 group. An alternative mechanism which could account for the change in stereoselectivity with different nucleophiles is for the reagent initially to attack the Fe centre or one of the CO ligands and then be transferred intramolecularly to the aldehyde which adopts an s-cis conformation.Owing to the opposite direction of attack this would then give rise to the Yendo product. Although less likely than a simple conformational change for the aldehyde this overall endo delivery cannot be entirely ruled out. Endo attack of a nucleophile on cyclohexadienyltricarbonyliron (+1) cationic complexes has been suggested when the addition of the nucleophile is a reversible process or when the reaction centre is substituted.18 Furthermore Brookhart et al. have reported quite different results concerning the addition of MeLi and Me2CuLi to (arene)tricarbonylmanganese (+1) cationic complexes.19 Whereas MeLi yields solely the exo addition product 22 reaction of Me2CuLi with arene complex 23 affords 3 MeO2C OH H R R H OH Fe(CO) 21 Yendo Fe(CO)3 20 Yexo RM adds to s- transconformation of the aldehyde Yexo:Yendo 80:20 85 67:33 80 65 0:100 Chemical Society Reviews 1998 volume 27 305 products resulting from apparent attack either at the metal centre or at one of the CO ligands (Scheme 5).Methyl transfer to the ring can be accomplished by heating the h1-methyl Mn complex 24 in the presence of PPh3. Me H 22 (+1) complex 23 Scheme 5 MeLi and Me2CuLi react quite differently with (arene)Mn(CO)3 4.2.2 Nucleophilic addition to aldehyde functionality in the side-chain of trimethylenemethane tricarbonyliron complexes Trimethylenemethane (TMM) complexes bearing aldehyde functionality have also been prepared and the few reported examples of their reaction with nucleophiles suggest similar patterns of reactivity and stereoselectivity to h4-diene complexes.The readily separable diastereoisomers are formed in high yield and the nature of the nucleophile again affects the stereochemical outcome of the addition (Scheme 6).20 O (CO) Mn(CO)3 306 Scheme 6 Diastereoselective addition of an organozinc reagent into aldehyde functionality in the side-chain of a (TMM)Fe(CO)3 complex 4.2.3 Nucleophilic addition to aldehyde functionality in the side-chain of p-allyltricarbonyliron lactone complexes The stereochemical outcome of the reaction of p-allyltricarbonyliron lactone complexes with organoaluminium nucleophiles strongly depends on the nature of the nucleophile (Scheme 7).11 Thus in the case of the addition of a phenyl group into the aldehyde functionality of complex 7 using PhAlMe2 as the nucleophile the addition product 25 was isolated in 26% yield (along with 36% of the product resulting from methyl group transfer) as a single diastereoisomer formed by addition of the nucleophile to the s-cis-conformation of the aldehyde anti to the tricarbonyliron moiety.This is in accord with the model proposed for the addition of nucleophiles into ketone functionality (Fig. 7). Conversely when Ph3Al was used as the nucleophile while the yield was much improved the diastereoselectivity of the reaction was almost completely Chemical Society Reviews 1998 volume 27 86% Me2CuLi MeLi 0 °C Mn(CO)3 Me Mn(CO)2 3 23 Me2CuLi 24 PPh PhH D –78 °C H Me Mn(CO)2(PPh3) O (CO)3Fe H CH2Br Mn(CO)2 Zn H OH OH H (CO)3Fe 3Fe 9:1 O O O Fe(CO) Fe(CO) 3 3 3 O O O RAlX2 Ph O OH H OH H Ph 26 25 7 nucleophile 25:26 PhAlMe2 100:0 26 Ph3Al 71 Scheme 7 The nature of the aluminium reagent affects the diastereoselectivity of the addition reaction to aldehyde functionality in the sidechain of lactone complexes reversed with the major product 26 being that which would result from addition of the nucleophile to the s-trans-conformation of the aldehyde.While a simple explanation for this observation is not readily forthcoming it provides a clear illustration that the nature of the nucleophile can have a profound effect on the relative stereochemical outcome of the addition event.A variety of other organoaluminium reagents were also investigated and while the stereoselectivity of the addition reaction was not always high the major product remained that deriving from addition of the nucleophile anti to the Fe(CO)3 moiety onto the s-cis-conformation of the aldehyde. When allylstannanes were reacted with the same aldehyde complex 7 under Lewis acid activation the diastereoselectivity of the reaction was found to be strongly temperature dependent. 11 Thus at 278 °C the levels of stereocontrol were negligible and a 1 1 mixture of homoallylic alcohol products 27 and 28 was obtained albeit in excellent combined yield.At increased temperature increased diastereoselection was observed with a maximum being obtained in the region 220 to 240 °C. The major diastereoisomer was that which would result from anti addition to the s-trans-conformation of the aldehyde. Upon raising the reaction temperature further diastereoselectivity dropped off slightly once again (Scheme 8). This example serves to highlight that careful manipulation of reaction conditions can lead to good levels of diastereocontrol. O O Fe(CO) Fe(CO) Fe(CO) 3 H 3 combined yield (%) 3 O O O 20:80 SnBu BF3•OEt2 H H OH 27 7 O Fe(CO)3 O OH H 28 temperature (°C) 27:28 combined yield (%) 25 14:86 100 –40 11:89 100 50:50 –78 100 Scheme 8 Temperature has a profound effect on the diastereoselectivity of the BF·OEt2-mediated addition of allyltributylstannane to aldehyde functionality in the side-chain of lactone complex 7 4.2.4 Conclusions Aldehyde groups are readily incorporated into the side-chains of the organic ligands of tricarbonyliron complexes and they react with a variety of nucleophilic reagents.Levels of diastereoselectivity are highly dependent on the exact reaction conditions employed and on the nature of the nucleophile since both these factors appear to affect the equilibrium between the s-cis and s-trans conformations of the substrate which in turn affects the stereochemical outcome of the reaction (assuming reaction always proceeds anti to the tricarbonyliron moiety).Nevertheless one important property which holds true in a remarkable number of cases is that the diastereoisomeric addition products can be readily separated from one another (vide infra) enabling facile access to diastereoisomerically pure complexes. 5 Secondary alcohol addition products adopt semi rigid conformations The Yendo and Yexo secondary alcohol addition products of tricarbonyliron complexes are usually readily separable by standard chromatographic techniques. This deserves a special mention as the Yexo product is invariably the more polar product regardless of the actual complex involved and of the nucleophile used. So reliable is this polarity difference between diastereoisomers that frequently stereochemical assignments can be made by analysis of Rf data alone.In a pioneering paper Clinton and Lillya proposed a model which accounted for the observed differences in polarity.9 They proposed that the a-sp3 centre of the diene ligand will adopt a staggered conformation in which the three sites are exposed to varying levels of steric crowding (Fig. 10). Position c is severely crowded by one of the H a H H b c Fe OC CO CO Fig. 10 The side-chains of h4-diene complexes adopt a preferential conformation CO ligands and the diene residue while position b suffers less steric crowding from two of the CO ligands. The preferred conformations of diastereoisomeric dienol complexes will therefore be those in which the hydrogen substituent adopts position c and the two larger groups (OH and alkyl) adopt positions a and b (Fig.11).These conformations (which are also relevant to analogous p-allyltricarbonyliron complexes) appear to be semi-rigid and can be used to account for the chromatographic behaviour of the two diastereoisomers. In the case of the Yexo products the exposed alcohol functionality allows extensive interactions with the stationary phase whereas the Yendo alcohol being more shielded interacts less strongly. As a result the Yexo complexes are invariably more polar than their Yendo counterparts. H H CH3 H OH H H H HO H3C H H Fe Fe OC OC CO CO Yexo Yendo CO CO Fig. 11 Yexo and Yendo complexes adopt preferential conformations 6 Addition of nucleophiles into h5-pentadienyltricarbonyliron (+1) cationic complexes Upon complexation of an organic ligand to a metal the normal patterns of reactivity for the free ligand are either repressed or more frequently reversed.This altering of the electronic properties of a substrate by metal complexation manifests itself in the opportunity not only to perform reactions which would normally be impossible on the non-complexed molecule but also to practice completely novel chemistry. In the case of h5-pentadienyltricarbonyliron (+1) cationic complex 29 the organic ligand is electrophilic in character. This is primarily a result of the negative charge stabilising properties of the tricarbonyliron group.In theory nucleophilic attack can occur at any of the five carbon atoms. In practice however only the outer carbon atoms are observed to react reaction at C2 or at C4 is relatively unusual and affords s,h3-allyl tricarbonyliron complexes 30 and 31 respectively.21 On steric grounds attack at the dienyl termini might be expected to be more favourable especially if this position is unsubstituted. This is indeed the case and results in the formation of h4-diene complexes 32 and 33 (Scheme 9). The transoid cationic complex 34 although not isolable is believed to be in equilibrium in solution with its more stable cisoid isomer 29 thus nucleophilic attack can proceed on either or both isomers affording (E,E)- and (E,Z)- isomeric h4-diene complexes 32 and 35 respectively (in the case of nucleophilic attack at C5) (Scheme 9).Nu R Fe(CO)3 H 30 Nu– 3 6 – 2 R 1 29 Fe(CO)3 Nu R PF PF 6 – H (CO)3Fe 33 R 34 Fe(CO) Fe(CO)3 4 5 3 R 35 Nu Scheme 9 Reaction of nucleophiles with h5-pentadienyltricarbonyliron (+1) cationic complexes affords a variety of products The regioselectivity of nucleophilic attack is often difficult to predict and the observed products are formed owing to a subtle interplay between electronic and steric effects imposed by substituents on the dienyl ligand. One example will serve to illustrate the problems of regioselectivity frequently encountered with these complexes. Donaldson et al. have investigated the reaction of malonate nucleophiles on C1-substituted h5-pentadienyltricarbonyliron (+1) cationic complexes (Scheme 10).22 In the case of methyl substituted complex 36 the reaction is non-regioselective with the malonate nucleophile attacking at either terminus of the dienyl ligand affording after chromatography h4-diene com- Chemical Society Reviews 1998 volume 27 Nu R Fe(CO)3 31 (CO)3Fe R 32 Nu 307 R¢ PF6 – Fe(CO)3 Li = R¢Li E E R Fe(CO)3 H E = CO2Me R a 36 - 39 R 36 Me 37 CO2Me 38 Ph 0 >92 0 0 39 p-MeOC6H4 Scheme 10 Reaction of lithium dimethyl malonate with C1-substituted h5-pentadienyltricarbonyliron (+1) cationic complexes plexes 36c and 36d (36c:36d 1 2).With ester substituted complex 37 however malonate addition occurs with almost complete regioselectivity at the C2 position to afford 37a (a small quantity of a product resulting from attack at C5 is also observed).When R is a phenyl group (38) products arising from addition at C1 C4 and C5 are observed in the ratio 25 2 3. In contrast when this is replaced by the more electron donating para-methoxyphenyl substituent (39) addition occurs with complete regiocontrol with attack at C1 exclusively. In the cases where a new stereogenic centre is produced the relative stereochemistry can be predicted by assuming exo attack of the nucleophile on the dienyl ligand. Pearson et al. have attempted to rationalise the regioselectivity of nucleophilic addition to unsymmetrically substituted pentadienyl complexes by proposing the addition to be under frontier orbital control although they also suggest that more subtle effects involving the steric demand of the substituent and incoming ligand in addition to Coulombic effects induced by the substituent can clearly have a marked influence on the regioselectivity of the reaction.23 Donaldson has also provided a rationalisation of the regioselectivity of the addition reactions of malonate nucleophiles to C1-substituted dienyl cationic complexes.22 Attack at the C2 position observed in the case of ester functionality at C1 is very unusual.Addition at this position (effectively a Michael addition) is probably a result of the strongly electron withdrawing nature of the ester group decreasing the energy of the LUMO of the dienyl ligand.This allows an improved energy match with the metal d atomic orbitals and therefore increased back donation of electron density on to the ligand. The overall result is that C2 becomes the most electrophilic centre. In contrast the electron donating capacity of the para-methoxy- Fe(CO)3 Fe(CO) HPF6 OH H R R isolable Fe(CO)3 R H Nu– Nu– already present to trap out cation Fe(CO)3 Nu H R Scheme 11 In situ trapping of cationic complexes by nucleophiles Chemical Society Reviews 1998 volume 27 308 Fe(CO)3 R¢ (CO)3Fe R¢ R R Fe(CO)3 H b c d ratio a b c d 33 67 0 <8 10 83 0 0 0 7 0 R 3 100 phenyl group at C1 raises the energy of the LUMO of the dienyl ligand.Nucleophilic addition of the ‘soft’ malonate anion is now under frontier orbital control and occurs at C1. For the cases of methyl and phenyl substituents on C1 (neither of which are strongly electron donating or withdrawing) nucleophilic attack is less regioselective affording a mixture of products. 6.1 Conclusions The reactions of nucleophiles with h5-pentadienyltricarbonyliron complexes are illustrative of the influence metal complexation can have on the reactivity of organic ligands. Although the resulting products are potentially useful regiocontrol is often poor unless strongly electron donating or withdrawing substituents are present on the ligand and this continues to limit their use in organic synthesis.7 A solution to the problems of regioselectivity—stereoselective C–C bond formation with h4-dienol tricarbonyliron complexes Metal complexation not only affects the reactivity of the organic ligand itself but may also have powerful effects on the chemistry of functional groups in the immediate vicinity of the ligand. Uemura et al. were first to realise that in situ trapping of the cationic complex generated from an h4-dienol complex might overcome the problems of regioselectivity described above (Scheme 11).24 Treatment of acetate complex 40 with AlEt3 or with allyltrimethylsilane in the presence of BF3·OEt2 resulted in the clean conversion to products 41 and 42 respectively (Scheme 12). The reactions were completely regioselective and significantly completely stereoselective.A mechanism can be proposed in which ionisation of the acetate PF6 – Fe(CO)3 HPF6 R¢ R H OH Fe(CO)3 H R transient transoid cation is configurationally stable over reaction Nu– time period Fe(CO)3 R H Nu Fe(CO)3 OAc H Me 40 Fe(CO)3 SiMe3 Me BF3•OEt2 H Me H 42 89% 43 73% AlEt3 Fe(CO) Fe(CO)3 3 H Me exo 41 Scheme 12 Formation of the transoid h5-pentadienyl cationic complex from 40 and subsequent reactions with nucleophiles through neighbouring group participation of the Fe(CO)3 moiety generates the transoid h5-pentadienyl cationic complex 43 which is trapped by the nucleophile attacking anti to the Fe(CO)3 group.The overall result is an SN1-type substitution which proceeds with complete retention of configuration. Roush and Wada have investigated the reaction in more detail.25 They have shown that ionisation of a free alcohol with BF3·OEt2 in the presence of TMSN3 or allyltributylstannane generates the substitution products in excellent yield without the need for conversion to the acetate. With less Lewis acidic nucleophiles such as AlMe3 substitution of the free alcohol is quite sluggish. However conversion to the acetate circumvents this problem and the reaction then occurs in excellent yield. Ester substituents on the diene ligand serve to deactivate the system presumably by interfering with carbocation formation. However conversion of the alcohol to the more labile chloroacetate again solves this problem and substitution typically occurs in excellent yield.In all cases elimination products are very minor if observed at all. Grée et al. have used this reaction to synthesise diastereoisomerically pure dienyl fluorides.26 Treatment of dienol Yexo complex 44 with diethylaminosulfur trifluoride (DAST) at 250 °C afforded fluoride 45 in 86% yield and with complete retention of configuration. Interestingly the corresponding Yendo complex 46 reacted in similarly high yield but was slightly less stereoselective with a small proportion of the apparent inversion product 45 being produced. The same result was observed with propargylic alcohol complexes the Y complex 47 reacted with complete retention of configuration whereas a 3 1 mixture of retention:inversion products 48 and 49 respectively was observed with the Yendo complex 50 (Scheme 13).There appears to be a difference in reactivity between Yexo and Yendo complexes with the former complexes exhibiting higher levels of stereocontrol. Consideration of the preferred conformations adopted by the side-chain carbinol centres provides some insight into this difference. One may postulate that the Yendo complex 46 initially forms cationic complex 51 which suffers from appreciable A1,3-allylic strain. If isomerisation to the more stable complex 52 (as formed by ionisation of the Yexo complex) occurs before the cation is trapped product 45 resulting from overall inversion of configuration would be observed (Scheme 14).The above rationale is based on the assumption that the Fe(CO)3 is an active neighbouring group in aiding ionisation of the a-centre. Another possibility which would also account for the small degree of stereochemical leakage in the Yendo series is that the a-centre also undergoes unassisted ionisation in its F DAST OH H E H E R R Fe(CO)3 Fe(CO)3 Yexo 44 R = Me 47 R = CH2CCH R R DAST H E E H OH F 45 R = Me 49 R = CH2CCH 3 Fe(CO)3 Yendo F H E 46 R = Me 50 R = CH2CCH R Fe(CO) Fe(CO) 3 E = CO2Me 96:4 3:1 86% 79% 45 49 R = Me 48 R = CH2CCH Scheme 13 Preparation of dienyl fluoride h4-complexes H Me Me H E E E Me H OH F H Fe(CO) 86% 79% 3 Fe(CO)3 Yendo 51 retention 46 Fe(CO)3 relief of A1,3 strain E = CO2Me F H E E Me Fe(CO)3 Fe(CO)3 45 52 inversion Scheme 14 A possible mechanism for the formation of the inversion product 45 preferred conformation (vide supra).27 In this case cationic complex 52 is formed directly and leads to the inversion product by nucleophilic trapping from the exo face (Scheme 15).E E Me H OH Fe(CO)3 Yendo (CO)3Fe Yendo 46 46 OH Me H Fe(CO)3 assisted ionisaton Me H E E H Me Fe(CO) unassisted ionisation 3 (OC)3Fe 52 51 inversion product retention product H Me 309 45 Scheme 15 An alternative mechanism for the formation of inversion product 45 7.1 Synthesis of heterocycles As an alternative to trapping the generated transoid cationic complex with an external nucleophile intramolecular nucleo- Chemical Society Reviews 1998 volume 27 philic trapping provides an interesting route to cyclic products.Treatment of diol complex 53 with HBF4 at 20 °C afforded a mixture of (E,E)- and (E,Z)-h4-diene complexes 54 and 55 possessing tetrahydropyran substituents. Complex 54 results from exo attack of the primary alcohol on the generated pentadienyl cation 56 (Scheme 16).28 Presumably isomerisation to the more stable cisoid geometry 57 is sufficiently rapid under the reaction conditions to compete with trapping of the cation hence the formation of the two (readily separable) products. Note that under the strongly acidic reaction conditions the possibility that product formation is a reversible process and the reaction is under thermodynamic control cannot be discounted.E 53 HBF4 Fe(CO) Fe(CO)3 3 E 56 Fe(CO)3 H E HO 57 Scheme 16 Stereoselective synthesis of tetrahydropyrans In a related system the tetrahydrofuran analogues 58 and 59 have been prepared by treating alcohol complexes 60 and 61 with HBF4 respectively. No products arising from isomerisation to a cisoid geometry were observed in this case which may be due to the kinetic favourability of five-membered ring formation resulting in a much more rapid trapping of the cation such that isomerisation is no longer a competing process (Scheme 17).28 This may also suggest that product formation is not reversible (but see below).55 23% Fe(CO)3 H OH E 60 Fe(CO)3 H E OH 61 E = CO2Me Scheme 17 Stereoselective synthesis of tetrahydrofurans Grée and Paquette have probed the cyclisation mechanism for tetrahydrofuran formation using 18O labelling studies.29 Treatment of diol complex 62 with Amberlyst 15 results in the complete loss of any label in the formation of the tetra- Chemical Society Reviews 1998 volume 27 310 H OH E = CO2Me OH Fe(CO)3 H E O 54 H 55% (CO)3Fe E H O H OH HBF4 E O O 58 63% Fe(CO) Fe(CO)3 3 HBF4 H E O 59 O 47% hydrofuran products 58 and 59 (Scheme 18). Under the reaction conditions employed two products are isolated with the major diastereoisomer 58 resulting from an apparent inversion of configuration.However the lack of a label in the product adds credence to an SN1-type substitution pathway being followed and suggests that the occurrence of two products is owing to equilibration under the reaction conditions. The authors suggest that the extended reaction time required for complete conversion allows the reverse reaction to proceed and with it the potential for s-bond rotation leading to a loss of stereoselectivity in spite of the nucleophile attacking exclusively anti to the Fe(CO)3 group. 16 OH Fe(CO)3 E 62 18OH H amberlyst 15 58% DCM 20 °C H E Fe(CO)3 16 59 O retention equilibration under reaction conditions Fe(CO)3 E H OH Scheme 18 Stereoselective synthesis of tetrahydrofurans 7.2 (Trimethylenemethane)tricarbonyliron complexes as a source of cross-conjugated pentadienyl cations Generation of a cation a to TMM complex 63 by standard treatment of an a-hydroxy group with BF3·OEt2 affords the corresponding cross-conjugated pentadienyl cation.In situtrapping of this cation with allyltrimethylsilane affords the ipso substitution products in high yield and with complete retention of configuration (Scheme 19).30 Complete regiocontrol is not always observed and the isoprene-type h4-diene complexes resulting from substitution at one of the unsubstituted termini of the cation are sometimes observed. However these sideproducts are usually minor and readily separable from the TMM products.Again even when tertiary carbocations are generated (e.g. from complex 64) elimination products are not observed. 7.3 p-Allyltricarbonyliron lactone complexes in nucleophilic substitution reactions Attempts to repeat this type of substitution reaction on p-allyltricarbonyliron lactone complexes have not met with success. Subjection of complexes bearing a-tertiary alcohol stereogenic centres to analogous reaction conditions results in dehydration and the resulting complexes bearing an olefinic side-chain are isolated in high yield. Clearly the presence of the lactone tether in this family of complexes has an effect on the ability of the tricarbonyliron moiety to stabilise positive charge a to the ligand and this is sufficient to favour a dehydration pathway.No reaction is observed in the case of secondary alcohol complexes. OH complete loss of 18O label retention:inversion 1.0:1.9 Fe(CO) E = CO2Me 3 E 58 inversion Fe(CO) H O 16 3 H E Me H OH (CO)3Fe 63 Me Me OH 64 Scheme 19 Allyltrimethylsilane reacts with cross-conjugated pentadienyl cations generated from trimethylenemethane complexes 7.4 Conclusions The unpredictable—and frequently low—regioselectivity in the reaction between nucleophiles and h5-pentadienyltricarbonyliron cationic complexes has led to the development of a modification of the reaction in situ nucleophilic trapping of the cation generated by ionisation of suitably functionalised h4-diene complexes.This not only removes the need for 78% Fe(CO)3 65 (CH2)3CO2Me i) OsO4 py ii) Na2S2O5 Fe(CO) 96% 3 OH (CO)3Fe RO RO 66 Fe(CO) (CH2)3CO2Me 3 R = TBDPS RO 67 Scheme 20 Preparation of diHETE metabolites utilising a stereoselective glycolation of functionalised h4-diene complexes 65 and 67 71 Me H BF3•OEt2 (CO)3Fe SiMe3 Me H Fe(CO)3 75:25 48% Me Me (CO)3Fe BF3•OEt2 SiMe3 (CO) (CH2)3CO2Me 3Fe RO s -cis conformer not significantly populated steps OH Bu (5 R,6 S)-diHETE 70 Fe(CO)3 (CH2)3CO2Me RO OH OH Bu (5 S,6 S)-diHETE isolation of the pentadienyl cationic complex intermediate but in most cases occurs with complete regiocontrol.The reaction is also highly stereoselective with the incoming nucleophile attacking the exo face anti to the sterically demanding Fe(CO)3 unit. The reaction occurs under mild conditions and the products are usually formed in high yields. Intramolecular trapping of the cation has been investigated leading to the preparation of tetrahydropyrans tetrahydrofurans and more recently tetrahydrothiopyrans and oxocenes.31,32 The reaction works equally well with trimethylenemethane complexes although in some cases complete regiocontrol is not observed. p-Allyltricarbonyliron lactone complexes do not undergo analogous reactions; only dehydration is observed in susceptible substrates. 8 Incorporation of olefin functionality in the side-chain of tricarbonyliron complexes The tricarbonyliron moiety acts as a highly efficient protecting group for diene functionality.Thus while any olefin in the sidechain of these complexes observes normal patterns of reactivity the protected diene remains intact. Again the steric bulk of the Fe(CO)3 group combined with the fact that side-chain appendages frequently adopt a preferential conformation ensures ample opportunity for stereoselective synthesis. 8.1 Asymmetric dihydroxylation Grée and co-workers have used a stoichiometric osmylation to effect glycolation of olefins directly attached to h4-diene complexes.33 (Note that although catalytic versions of the dihydroxylation reaction are compatible with the organometallic unit diol products are usually contaminated with ketols OH (CH2)3CO2H OH i) OsO4 py (CO)3Fe HO ii) Na2S2O5 98% (CH2)3CO2Me (CH2)3CO2Me OH RO 69 s -cis conformer significantly populated 9:1 Fe(CO)3 OH steps (CH2)3CO2H RO 68 (CH2)3CO2Me 311 HO Chemical Society Reviews 1998 volume 27 4 on resulting from over-oxidation).Since the Fe(CO)3 moiety is acting as a protecting group for the diene the overall outcome of the reaction is complete regiocontrol in the dihydroxylation of a triene. Excellent stereocontrol is observed in the case of cis olefin complex 65 with only one diol product 66 being isolated. In the case of its trans isomer 67 a separable 9:1 mixture of diols 68 and 69 is produced again in excellent yield (Scheme 20).In both cases the major product derives from attack of the OsO the olefin anti to the Fe(CO)3 unit. The olefin functionality preferentially adopts an s-trans conformation to minimise steric interactions between the side-chain and ligand. However in the case of trans olefin complex 67 even the s-cis conformation doesn’t suffer from excessive steric repulsions. As a result both conformations may be adopted although the product deriving from attack on the more heavily populated s-trans conformer predominates. This high yielding stereoselective glycolation has been successfully applied to the total syntheses of the arachidonic acid metabolites (5R,6S) and (5S,6S)-diHETE 70 and 71 respectively (Scheme 20).33 p-Allyltricarbonyliron lactone complexes have also been briefly investigated as a source of stereocontrol in an asymmetric dihydroxylation reaction.Treatment of olefin complex 72 with OsO4 in pyridine afforded a 4 1 mixture of diastereoisomeric diols 73 and 74 with the major product resulting from anti attack of the OsO4 reagent on the s-trans-conformation of the olefin in a completely analogous fashion to that reported for h4-diene complexes (Scheme 21). O O 3 3 O O C5H11 C5H11 72 72 OsO4 py O O Fe(CO) Fe(CO) Fe(CO) 3 Fe(CO) 3 O O OH OH 64% C5H11 C5H11 OH OH 4:1 73 74 Scheme 21 Olefin functionality in the side-chain of p-allytricarbonyliron complex 72 undergoes stereoselective dihydroxylation 8.2 Enone functionality in the side-chain of h4-diene complexes h4-Diene complexes bearing a,b-unsaturated carbonyl functionality in the side-chain have been prepared.They preferentially adopt the s-trans conformation thereby minimising steric interactions with the diene ligand. The powerful blocking capability of the Fe(CO)3 unit has been utilised to perform a highly stereoselective 1,4-addition reaction in Grée’s total synthesis of (2)-verbenalol 75 (Scheme 22).34 Treatment of highly reactive enone 76 with MeMgI at 240 °C in THF produced the 1,4-addition product 77 in excellent yield and as a single diastereoisomer. Further manipulations led to (2)-verbenalol 75.34 Again partial complexation of the trienone by the Fe(CO)3 unit ensures the exclusive formation of the 1,4-addition product 77.8.3 Incorporation of dienophiles in the side-chain of h4-diene complexes The same precursor 76 has also been used in a Diels–Alder reaction with 2,3-dimethylbutadiene.35 Heating at reflux in THF for 12 h resulted in the isolation of the Diels–Alder adduct 78 in Chemical Society Reviews 1998 volume 27 312 Me H O O MeMgI E (CO)3Fe E (CO)3Fe O –40 °C THF O O 93% O O 77 76 FeCl3 10 equiv. E = CO2Me MeCN –15 °C 92% OH O O steps E O O H O Me O O CO2Me (–)-verbenalol 75 Scheme 22 Use of a stereoselective Michael reaction in the synthesis of (2)-verbenalol 70% yield arising from exo addition of the diene to the s-transconformation of the dienophile (Scheme 23). O MeO2C (CO)3Fe O O 76 O 12 h THF 65 °C 70% O MeO2C (CO)3Fe O O 78 O Scheme 23 Stereoselective Diels–Alder reaction 8.4 Conclusions Incorporation of olefin functionality into the side-chain of h4-diene complexes has been achieved.Again the minimisation of steric interactions between the ligand and the side-chain ensures the preferential adoption of one conformation by the appendage. This in association with the steric blocking ability of the Fe(CO)3 group provides an efficient means for stereocontrol in a number of typical reactions of olefins. 9 Tricarbonyliron complexes in asymmetric synthesis—a summary Tricarbonyliron complexes bearing a wide variety of functional groups as side-chain appendages can be prepared in enantiomerically enriched form.The Fe(CO)3 group acts as a sterically bulky unit directing the facial attack of reagents onto functional groups in the side-chain of the ligand. Steric interactions between the ligand and the side-chain appendage cause olefin and carbonyl functional groups preferentially to adopt one conformation. The degree of steric blocking by the Fe(CO)3 moiety seems to be absolute with reagents approaching anti to the steric encumbrance. The nature of the functional group a to the ligand dictates the population of conformers with ketones and some olefinic substrates behaving as though only one reactive conformation is adopted and giving rise to excellent CO2Pri O B CO2Pri Fe(CO)3 O OHC OHC molecular sieves toluene –78 °C 90% >98% ee Fe(CO)3 H FeCl3 MeCN –15 °C H O then H2O pentan-3-one then CH2N2 O O CO2Me O 70% 83 CHO steps HN OMe MeO known HN OHC 84 levels of stereocontrol.Aldehydes appear to be less conformationally biased although good to excellent levels of stereocontrol may still be obtained by careful choice of reagents and manipulation of reaction conditions. The ability of the tricarbonyliron moiety to affect the reactivity of functionality in the side-chain is exemplified by the nucleophilic substitution reactions of h4-diene and trimethylenemethane complexes in which products deriving exclusively from an SN1-type substitution process are produced with the tricarbonyliron group participating in cation stabilisation in addition to acting as a blocking group to ensure excellent levels of stereocontrol.This balance is a fine one and in analogous reactions with p-allyltricarbonyliron complexes the only products isolated are those resulting from dehydration. A final example by Roush and Wada exemplifies how tricarbonyliron complexes can be elegantly incorporated into modern synthetic design.36 In his formal synthesis of ikarugamycin 79 Roush first utilises a face and group selective desymmetrisation using a tartrate-derived allylboronate reagent to obtain the enantiomerically enriched starting material 80. Modification of a side-chain then affords a Michael acceptor 81 which is used in a highly stereoselective 1,4-addition reaction affording 82. Finally generation of the transoid pentadienyl cationic complex with in situ-trapping with an organoaluminium reagent installs another stereocentre and forms 83.Efficient decomplexation another important characteristic of tricarbonyliron complex chemistry allows for the preparation of the indacene unit 84 of ikarugamycin 79 (Scheme 24). Scheme 24 Roush’s approach to ikarugamycin 79 79 4 R. B. King in The Organic Chemistry of Iron eds. E. A. Koerner von Gustorf F.-W. Grevels and I. Fischler Academic New York 1978 vol. 1 pp. 525–625. 5 R. Grée and J. P. Lellouche in Advances in Metal-Organic Chemistry ed. L. S. Liebeskind Jai Greenwich 1995 vol. 4 pp. 129–273. 6 R. Aumann H. Ring C. Krüger and R. Goddard Chem. Ber. 1979 112 3644. 7 Y. Gao R. M. Hanson J.M. Klunder S. Y. Ko H. Masamune and K. B. Sharpless J. Am. Chem. Soc. 1987 109 5765. 8 H. C. Kolb M. S. VanNieuwenhze and K. B. Sharpless Chem. Rev. 1994 94 2483. 9 N. A. Clinton and C. P. Lillya J. Am. Chem. Soc. 1970 92 3058. 10 S. V. Ley L. R. Cox G. Meek K.-H. Metten C. Piqué and J. M. Worrall J. Chem. Soc. Perkin Trans. 1 1997 3299. 11 S. V. Ley S. Burckhardt L. R. Cox and G. Meek J. Chem. Soc. Perkin Trans. 1 1997 3327. 12 M. Franck-Neumann P. Chemla and D. Martina Synlett 1990 641. 13 S. V. Ley and G. Meek J. Chem. Soc. Perkin Trans. 1 1997 1125. 14 S. V. Ley and L. R. Cox J. Chem. Soc. Perkin Trans. 1 1997 3315. 15 R. B. King T. A. Manuel and F. G. A. Stone J. Inorg. Nucl. Chem. 1961 16 233. 16 R. Grée Synthesis 1989 341. 17 K. Nunn P. Mosset R. Grée and R. W. Saalfrank Angew. Chem. Int. Ed. Engl. 1988 27 1188. 18 A. J. Birch and A. J. Pearson Tetrahedron Lett. 1975 2379. 19 M. Brookhart A. R. Pinhas and A. Lukacs Organometallics,1982 1 1730. 20 M. Franck-Neumann D. Martina and M.-P. Heitz Tetrahedron Lett. 1989 30 6679. 21 S. G. Davies M. L. H. Green and D. M. P. Mingos Tetrahedron 1978 34 3047. 22 W. A. Donaldson L. Shang C. Tao Y. K. Yun M. Ramaswamy and V. G. Young Jr. J. Organomet. Chem. 1997 539 87. 23 A. J. Pearson T. R. Perrior and D. C. Rees J. Organomet. Chem. 1982 226 C39. 24 M. Uemura T. Minami Y. Yamashita K. Hiyoshi and Y. Hayashi Tetrahedron Lett. 1987 28 641. 25 W. R. Roush and C. K. Wada Tetrahedron Lett. 1994 35 7347. 26 D. M. Grée C. J. M. Kermarrec J. T. Martelli R. L. Grée J. P. Lellouche and L. J. Toupet J. Org. Chem. 1996 61 1918. 27 N. A. Clinton and C. P. Lillya J. Am. Chem. Soc. 1970 92 3065. 10 References 1 A. J. Pearson Iron Compounds in Organic Synthesis (Best Synthetic Methods Series) eds. A. R. Katritzky O. Meth-Cohn and C. W. Rees Academic London 1994. 2 S. G. Davies Organotransition Metal Chemistry Applications to Organic Synthesis (Organic Chemistry Series) ed. J. E. Baldwin FRS Pergamon Oxford 1982. 3 S. V. Ley L. R. Cox and G. Meek Chem. Rev. 1996 96 423. 3 OH Fe(CO)3 O OH Meldrum's acid py 92% O O 80 O 81 MgBr Fe(CO) THF –78–0 °C 83–88% Fe(CO)3 i) Ac2O py DMAP DCM H OH ii) AlEt3 DCM –20–23 °C O 69–75% O O O 82 O OH O ikarugamycin O 313 Chemical Society Reviews 1998 volume 27 28 A. Teniou L. Toupet and R. Grée Synlett 1991 195. 29 D. Grée R. Grée T. B. Lowinger J. Martelli J. T. Negri and L. A. 30 M. Franck-Neumann A. Kastler and P.-J. Colson Tetrahedron Lett. 31 A. Hachem L. Toupet and R. Grée Tetrahedron Lett. 1995 36 32 D. M. Grée J. T. Martelli R. L. Grée and L. J. Toupet J. Org. Chem. Paquette J. Am. Chem. Soc. 1992 114 8841. 1991 32 7051. 1849. 1995 60 2316. Chemical Society Reviews 1998 volume 27 314 33 J. P. Lellouche A. Gigou-Barbedette and R. Grée Bull. Soc. Chim. Fr. 1992 605. 34 M. Laabassi and R. Grée Tetrahedron Lett. 1988 29 611. 35 T. Benvegnu J. Martelli R. Grée and L. Toupet Tetrahedron Lett. 1990 31 3145. 36 W. R. Roush and C. K. Wada J. Am. Chem. Soc. 1994 116 2151. Received 20th April 1998 Accepted 13th May 1998