2 Synthetic methods Part (ii) Pericyclic methods By PAUL J. STEVENSON School of Chemistry The Queen’s University of Belfast Belfast Northern Ireland BT9 5AG 1 Diels–Alder reaction Catalysis Cationic chiral C 27 symmetric bis(oxazoline) copper complex 1 is finding application as a Lewis acid catalyst in a number of natural product syntheses which involve both inter- and intra-molecular Diels–Alder reactions of a,b-unsaturated imides as the key step (Scheme 1). The nature of the anion is important with hexafluoroantimonate giving both higher reactivity and better ee values. Chelation of both carbonyl groups of the imide to the metal prior to cycloaddition is an important feature of this chemistry. Hence a one molar solution of triene 2 in methylene chloride underwent intramolecular Diels–Alder reaction at 0 °C over 24 h in the presence of 5mol% catalyst 1 and gave cycloadduct 3 in 81% yield without any competition from intermolecular reactions.1 The endo/exo diastereoselection was greater than 99 1 and the ee of adduct 3 was 96%.Adduct 3 has both the correct relative and absolute stereochemistry at the four newly generated chiral centres for elaboration to isopulo’upone. Intermolecular Diels–Alder reaction of furan with a,b-unsaturated imide 4 using 5mol% of copper catalyst 1 in methylene chloride as solvent at[78 °C for 42 h gave the endo adduct 5 with 97% ee.2 The endo exo ratio was a disappointing 4 1 but the major isomer was isolated in 67% yield by a single crystallisation. A major drawback with this procedure is maintaining a low temperature for a very long reaction time.Although the reaction is complete after 2.5 h at [20 °C the endo exo ratio drops to 2 1 and the ee to 59%. Interestingly the exo-isomer is racemic. Adduct 5 was converted to ent-shikimic acid in six additional steps. 1-Acetoxy-3-methylbuta- 1,3-diene undergoes Diels–Alder reaction with imide 4 at [20 °C in methylene chloride in the presence of 2mol% of copper catalyst 1 and gave a 73 27 mixture of exo endo isomers with 97% ee for the exo-isomer 6.3 The additional methyl group in the 3-position in the diene is interacting with the ligand and this is reversing the endo selectivity usually observed for these reactions. The exo-isomer crystallises and can be isolated in 57% yield. This was converted to ent-tetrahydrocannabinol in four additional steps. All manipulations of copper catalyst 1 were carried out in a dry box.Only the S,S-bis(oxazoline) ligand was used in these studies even though in two cases it gave the opposite enantiomer of the natural product. This suggests that the S,S-enantiomer of the bis(oxazoline) ligand is much more readily available than the R,R-enantiomer. 19 O N O N But But Cu N O O O O O H N O O O H H TBSO O N O O TBSO O N O O OAc O O N O AcO 6 (iii) (ii) (i) 4 5 3 2 1 2 SbF6 – 2+ Scheme 1 Reagents (i) 5mol% 1 0 °C; (ii) 5mol% 1 [78 °C; (iii) 2mol% 1[20 °C Bis(oxazoline) magnesium complex 7a 10 mol% catalyses the Diels–Alder reaction of cyclopentadiene with a,b-unsaturated imide 4 in methylene chloride at[80 °C. The products of this reaction have an endo exo ratio of 96 4 and a 73% ee in favour of the S-enantiomer for the endo isomer (Scheme 2).4 Incredibly the ee reverses to give predominantly the oppositeR-enantiomer with an ee of 73% when water or alcohol is added to the reaction medium.These results can be rationalised by invoking chelation of the hydroxy group of the additive to magnesium with a change in geometry from tetrahedral to octahedral when the imide binds. This is the first example of an achiral auxiliary reversing the ee of a bis(oxazoline) catalyst. With catalyst 7b the endo exo ratio increases to 99.5 0.5 with 97% ee S for the endo adduct representing the best stereocontrol reported to date in these systems. Water and ethanol with this catalyst decrease the ee to 78% S and 76% S respectively. From a general practical viewpoint it is worrying that adventitious water or small amounts of alcohol added to stabilise 20 P.J. Stevenson O N O N Mg Ph R Ph R O O N O N O O O 4 2ClO4 – 7a R = H 7b R = Ph 2+ + Scheme 2 O O O (ii) (i) 10 9 8 Scheme 3 Reagents (i) ZnCl 2 ; (ii) 6]BF 3 chlorinated solvents can catalytically produce the undesired enantiomer hence lowering the overall ee in reactions of intrinsically high ee. Methylrhenium trioxide (abbreviation MTO) 1 mol% catalyses Diels–Alder reactions of a,b-unsaturated aldehydes and ketones with dienes in chloroform or water at room temperature.5MTOis acting as a Lewis acid and has the big advantage that it is neither air nor water sensitive and does not produce protonic acid on hydrolysis. Hence reaction of isoprene with methyl vinyl ketone in chloroform proceeds at room temperature in the presence of 1mol%MTOand gave the Diels–Alder adduct in 90% yield after 2.5 h with the expected regiochemistry.In the absence of added dienophile MTO catalyses self Diels–Alder reaction of the dienes over one week. A recent approach to the Taxol™ A,B,C-ring system is based on coupling a bis-diene 8 to a bis-dienophile penta-1,4-dien-3-one in two consecutive Diels–Alder reactions (Scheme 3).6 The chemoselectivity of the initial intermolecular Diels–Alder reaction is controlled by the substitution pattern on the dienes with the least substituted diene participating in the intermolecular Diels–Alder reaction. This proceeded in methylene chloride at 25 °C in the presence of a catalytic amount of zinc chloride and gave exclusively the endo adduct 9 in 63% yield. The second step involved intramolecular Diels–Alder reaction between the more highly substituted diene 9 and the pendant dienophile.This proceeded in toluene at[78 °C and warming to 0 °C in the presence of six equivalents of boron trifluoride. The tricyclic compound 10 was isolated in 82% yield as a single diastereoisomer (albeit the wrong one for Taxol™). Although it looks as though these two steps should be achievable in a single operation neither Lewis acid was capable of catalysing both the inter- and the intra-molecular Diels–Alder reactions. Z-Penta-2,4-diene is a notoriously di¶cult diene to get to participate in Diels–Alder reactions. With Lewis acid catalysts it readily polymerises even at low temperatures. It 21 Synthetic methods Part (ii) Pericyclic methods O O O NO2 O O NO2 O AcO CHO R2 R3 R1 R1 CHO R3 R2 OAc (ii) (i) + 11a R1 = H R2 = Me R3 = CH2OTBS 12a,b 11b R1 = R2 = R3 = Me 13 11b Scheme 4 Reagents (i) Me 2 AlCl; (ii) BCl 3 2,6-di-tert-butylpyridine is generally accepted that all Z-dienes will be poor partners for Diels–Alder chemistry.This myth has now been challenged and it is reported that Z-dienes with additional alkyl groups are excellent partners for Lewis acid catalysed Diels–Alder reactions (Scheme 4).7 Hence diene 11a reacted with acetoxyacrolein in methylene chloride at [80 °C in the presence of dimethylaluminium chloride and gave 12a in 75% yield ratio endo exo 96 4. For diene 11b the regiochemistry was excellent and gave a workable 60% yield of 12b with a tertiary centre adjacent to a geminal dimethyl group. Presumably the additional alkyl groups attached to these dienes gave them extra stability.2,6-Di-tert-butylpyridine 25 mol% in combination with boron trichloride 110 mol% has also been used to promote reactions of diene 11b with dienophiles in methylene chloride at 25 °C to give Taxol™ ring A precursors 13 in 99% yield.8 It is believed that 2,6-di-tert-butylpyridine is acting as a proton scavenger hence protecting the diene from decomposition but that it is bulky enough not to react with the Lewis acid. Dienes with Lewis acidic appendages 14 undergo rapid intermolecular Diels–Alder reactions with fumarate esters in tetrahydrofuran at 25 °C and gave cycloadduct 15 in 51% yield endo exo ratio 4 1 (Scheme 5).9 Chelation of the ester carbonyl group to the aluminium makes the cycloaddition pseudo intramolecular and hence allows the mild reaction conditions.On the same theme titanium enolates of a,b-unsaturated aldehydes reacted with N-benzylmaleimide in toluene–isopropan-2-ol at [15 °C and gave exclusively the endo adducts 16a and 16b ratio 9 1 in 90% overall yield.10 The acetate 16b is the ‘normal’ Diels–Alder product whereas the alcohol 16a is derived from the titanium enolate. When 1.2 equivalents of NpTADDOL were added to the reaction the alcohol 16a was produced with an ee of 90%. Interest continues in metallated dienes which give allyl metal derivatives on cycloaddition (Scheme 6). Boronate 17 reacts with ethyl acrylate in methylene chloride at 25 °C in the presence of ethylaluminium dichloride and gave a cycloadduct with an endo exo ratio greater than 95 5.11 The isolated allyl boronate could be reacted further with propanal and gave a 1,4-disubstituted cyclohexene 18 in 67% overall yield for the two steps.In a similar fashion silicon-substituted diene 19 reacted with ethyl acrylate in methylene chloride at[60 °C with titanium tetrachloride one equivalent 22 P. J. Stevenson OH CO2Me CO2Me O O OMe MeO O AlMe2 OR N O O Ph N O O Ph O Ac (ii) (i) 16a R = OH 16b R = OAc 15 14 Scheme 5 Reagents (i) 25 °C; (ii) Ti(OPr*) 4 CO2Et HO CO2Et B O O CO2Et B O O CO2Et Ph2MeSi CO2Et CO2Et OH OH (iii) (ii) (i) 21 20 19 18 17 Scheme 6 Reagents (i) EtAlCl 2 20 °C; (ii) EtCHO; (iii) TiCl 4 ,Me 2 AlCl 2 ,[60 °C then EtCHO and 20mol% dimethylaluminium chloride as Lewis acids and gave an intermediate allylsilane product.12 Propanal was added to the reaction mixture at [60 °C and the stereoisomeric adducts 21 and 22 were isolated as a 4 1 mixture in 60% overall yield.The Lewis acids are catalysing both the Diels–Alder and the allylation reactions. Anthracenebisresorcinol in the solid state forms a hydrogen bonded network with cavities in which small polar molecules can be bound; 1.7mol% of this solid catalyses the Diels–Alder reaction of neat cyclohexa-1,3-diene with acryloin at 25 °C.13 The catalyst is insoluble in the reaction medium and the endo Diels–Alder adduct was obtained in unspecified yield. 23 Synthetic methods Part (ii) Pericyclic methods N N M O Ph N N M Ph N N O O Ph O 22a M = Cr(CO)4 22b M = W(CO)4 23 24 (i) (ii) Scheme 7 Reagents (i) 45 °C CH 2 Cl 2 ; (ii) (NH 4 ) 2 Ce(NO 3 ) 6 O NMe2 TSBO NMe2 CHO TSBO Me2N CHO (i) (ii) 25 26 27 Scheme 8 Reagents (i) KN(SiMe 3 ) 2 Bu 3 SiCl; (ii) PhMe 20 °C Intermolecular Diels–Alder reaction A major current problem in Diels–Alder chemistry is the production of exo-cycloadducts with high ee.The use of chiral chromium 22a and tungsten 22b carbene complexes as dienophile goes some distance to solving this problem (Scheme 7).14 Hence complex 22a reacted with penta-2,4-diene in methylene chloride at 45 °C for 60 h and gave 23a in 48% yield ratio 84 16 exo endo products. The de for the exo product was greater than 99%. With the more reactive Danishefsky diene the Diels–Alder adduct was isolated in 80% yield ratio exo endo 96 4 de greater than 99%. Finally the metal can be oxidatively removed with ceric ammonium nitrate and gave the formal exo products 24 from an a,b-unsaturated imide. An aza analogue of the Danishefsky diene has recently been reported (Scheme 8).15 The vinylogous amide precursor 25 was readily prepared from dimethylamine and commercially available 4-methoxybut-4-en-2-one.Treatment of 25 with potassium hexamethyldisilazide at low temperature followed by tributylsilyl chloride gave the diene 26 in quantitative yield. It appears that this diene is more reactive than Danishefsky’s diene and it reacts with methacrolein at 20 °C in toluene to give cycloadduct 27 in 87% yield as a single regioisomer endo exo ratio 25 1. A chiral version of this reaction has also been reported in which the dimethylamino group is substituted for 2,5-diphenylpyrrolidine.16 In this case the same reaction proceeded at 0 °C to give a product with a de of 85%. Cyclohexenes are usually poor dienophiles even when activated with electron withdrawing groups.Boryl groups are emerging as powerful neutral activating groups for dienophiles. The reactivity can be tuned by the choice of the other groups attached to boron. Stock solutions of the dibromoboryl alkenes are readily available by treating the corresponding vinyl stannanes with boron tribromide. The dibromoboryl group activates cyclohexene to undergo Diels–Alder reaction with isoprene in hexane at 25 °C for 8 h (Scheme 9).17 Oxidative workup gave the cis-decalin 28 in 66% overall yield. 24 P. J. Stevenson Br2B H OH 28 (i) (ii) Scheme 9 Reagents (i) 25 °C hexane; (ii) Et 3 N then H 2 O 2 NaOH O CO2Et OEt O H CO2Et OEt (i) 29 30 Scheme 10 Reagents (i) 90 °C in a sealed tube Inverse electron demand Diels–Alder reaction with dienes containing two electron withdrawing groups working in synergy with electron rich alkenes has been investigated (Scheme 10).18 Hence reaction of 29 with a tenfold excess of ethyl vinyl ether 90 °C in a sealed tube for 24 h gave exclusively the endo cycloadduct 30 in quantitative yield.A new ketene equivalent a-cyano-2,4-dinitrophenylcarboxylate has being reported. 19 This is readily prepared in 62% yield by reaction of acyl nitriles with 2,4-dinitrobenzoyl chloride. It is 5–6 times more reactive than acetoxyacrylonitrile and reacts with cyclopentadiene in acetonitrile at room temperature to give the Diels–Alder adduct in 95% yield. Hydrolysis of the ester with one molar aqueous sodium hydroxide generates the cyanohydrin which collapses to a ketone. Control of exo/endo-selectivity can be di¶cult in Diels–Alder reactions of 1-oxgenated- 1,3-dienes with 2-nitroacrylates.However the choice of the substituent on oxygen has been shown to have a dramatic e§ect on controlling the exo/endoselectivity. 20 Acyl was found to be better than alkyl or silyl and 1-acetoxybuta-1,3- diene reacted with methyl 2-nitroacrylate in dichloromethane at room temperature and gave a 71% yield of cycloadduct with endo exo ratio greater than 95 5. Hetero Diels–Alder reactions Indium trichloride 20 mol% catalyses the imino Diels–Alder reaction of cyclohexenone with aromatic imines 31 at 25 °C in acetonitrile and gave the regioisomeric products 32 33 ratio 2.2 1 in 65% overall yield (Scheme 11).21 With cyclopentadiene as dienophile product 34 was isolated in 75% yield after 30 min.The reaction of Danishefsky type dienes with aldehydes continues to attract attention. In reactions with chiral aromatic aldehydes it has been shown that the de of the cycloadduct can be controlled to some extent by the size of the lanthanide metal catalyst. Lanthanides of greater ionic radii gave the best des.22 Chiral tris-1,1@-binaphthyl- 2,2@-diylphosphate ytterium 10mol% catalyses the hetero Diels–Alder reaction of aromatic aldehydes with Danishefsky’s diene in methylene chloride at room temperature and gave cycloadducts in both high yield 86% and ee 93% (in the case of 25 Synthetic methods Part (ii) Pericyclic methods NH O O N Ph NH Ph O NH Ph Ph 31 32 33 34 (i) (ii) Scheme 11 Reagents (i) InCl 3 ; (ii) cyclopentadiene N O Et N N Et O Ph O N H Ph (i) 36 35 Scheme 12 Reagents (i) PhNCO CH 2 Cl 2 25°C 4-methoxybenzaldehyde).23 To date all other catalysts required low temperatures to achieve good ees for this reaction.One disadvantage is that each mole of catalyst requires three moles of 1,1@-bi-2-napthol and a heavy loading 10 mol% of catalyst is required. Chiral 1-azadiene 35 reacts with two equivalents of phenyl isocyanate in methylene chloride at 25 °C over 48 h and gave the 2 1 cycloadduct 36 in 58% yield as a single diastereoisomer (Scheme 12).24 This is a rare example of e¶cient 1,5-asymmetric induction. Intramolecular Diels–Alder reactions In model studies directed towards the synthesis of squalene synthase inhibitor CP225 917 the Lewis acid catalysed intramolecular Diels–Alder reaction of triene 37 was investigated (Scheme 13).25 This reaction proceeded in methylene chloride at[10 °C in the presence of 0.5 equivalents of dimethylaluminium chloride and gave the cycloadduct 38 in 86% yield as a 3 1 mixture of stereoisomers.The most significant aspect of this reaction is that the intramolecular reaction competes favourably with the intermolecular one even though the product of the former reaction contains a double bond at a bridgehead. The rings in this bridged bicyclic system are obviously large enough to 26 P. J. Stevenson O OBn MeO O Et Et BnO MeO (i) 38 37 Scheme 13 Reagents (i) Me 2 AlCl O NH N TfO N NC N NC H N NC H (iii) (ii) (i) 41 40 39 Scheme 14 Reagents (i) Tf 2 O; (ii) LiCN 12-crown-4; (iii) 110 °C PhH accommodate this allowing rapid entry to this novel ring system. 1-Aza-1,3-dienes are potentially useful dienes for intramolecular Diels–Alder cycloadditions.However in general yields are low due to the formation of side products and the instability of the adducts. The introduction of a 2-cyano-substituent into 1-aza-1,3-dienes gave much cleaner Diels–Alder reactions.26,27 a,b-Unsaturated amides are readily converted to 1-aza-2-cyano-1,3-dienes by treating the corresponding imidoyl triflate in tetrahydrofuran with lithium cyanide in the presence of 12-crown-4 (Scheme 14). Although the overall yield for the two step process is not very high 42% the starting materials are readily available. The 1-aza-2-cyano-1,3-diene 39 is stable enough to be isolated and undergoes intramolecular Diels–Alder reactions when heated in benzene at 110 °C in a sealed tube and gave the bicyclic products 40 41 in 94% combined yield ratio 4 1.An e¶cient synthesis of xestoquinone is based on an interesting intramolecular Diels–Alder reaction (Scheme 15).28 Treatment of 2-methoxy-4-methylphenol with a fourfold excess of penta-2,3-dien-1-ol and bis(trifluoroacetoxy)iodobenzene as oxidant in tetrahydrofuran gave an intermediate 42 which contains two diene moieties. The major product from the Diels–Alder reaction 43 61% yield is the one in 27 Synthetic methods Part (ii) Pericyclic methods OH OMe O O O Me HO O H H O H (iii) (ii) (i) 42 44 O O OMe 43 + Scheme 15 Reagents (i) PhI(OCOCF 3 ) 2 ; (ii) 60 °C; (iii) trimethylbenzene 175 °C EtO2C EtO2C OH H EtO2C EtO2C H 45 (i) (ii) Scheme 16 Reagents (i) (c-C 6 H 11 ) 2 BH; (ii) trimethylamine N-oxide which the cyclic diene behaves as the diene and one of the double bonds of the acyclic diene behaves as the dienophile.The required product 44 in which the acyclic diene behaves as the diene and the cyclic diene behaves as the dienophile is formed in a miserable8% yield. However if 43 is heated in boiling trimethylbenzene it undergoes a [3,3]-sigmatropic rearrangement and gave the required adduct 44 in 81% yield. Therefore it is possible to obtain 44 in 56% overall yield from 2-methoxy-4-methylphenol by this route. Others have independently published very similar chemistry.29 A thermal intramolecular Diels–Alder reaction which gave endo-selectivity has been reported (Scheme 16).30 This was achieved by the introduction of boron into the dienophile by chemoselective hydroboration of an alkyne in the presence of the diene using dicyclohexylborane.The boron substituent activates the alkene and the intramolecular Diels–Alder reaction proceeds in refluxing benzene overnight and gave after oxidative workup the endo trans ring junction product 45 in 44% isolated yield. 28 P. J. Stevenson O R R O O H H O N2 O H O R R C O+ O H 48 46a R = H 46b R = Me 47 46 – (i) Scheme 17 Reagents (i) Rh(OAc) 2 CH 2 Cl 2 25°C 2 1,3-Dipolar cycloadditions Dipolar cycloaddition of transient oxonium ylides followed by cleavage of the carbon –oxygen bond is emerging as a powerful method in the synthesis of fused ring carbocycles. The oxonium ylides are invariably generated by reaction of transition metal carbene complexes with carbonyl compounds. In turn the carbene complex is generated by reaction of a carbonyl stabilised diazo compound with a transition metal complex usually of rhodium.Two groups have independently used this approach to synthesise the indane ring skeleton common to the anti-tumour illudalanes sesquiterpenes (Scheme 17).31–33 Oxonium ylide 47 generated from the diazo compound reacted with cyclopentenones 46a,b in methylene chloride at room temperature and gave the adducts 48a,b in 52% and 40% yields respectively. A major feature of this chemistry is the highly regioselective nature of the 1,3-dipolar cycloadditions and the mild reaction conditions to which the cyclopropyl groups are stable. Unactivated alkenes undergo intramolecular dipolar cycloaddition with oxonium ylides in boiling benzene at 50 °C for 4 h producing multiple fused ring systems from simple precursors (Scheme 18).Hence for substrates 49 and 51 carbene reaction with the imide carbonyl generates one ring and the intramolecular cycloaddition generates another two rings and gave 5034 and 5235,36 in 95% yields and 97% yields respectively. Adducts 50 and 52 are interesting in that they are precursors to N-acyl iminium ions. This chemistry was exploited in the conversion of 52 to lycopodine. The scope of this strategy was considerably widened when chiral rhodium carboxylate complexes 1 mol% were used to generate the oxonium ylide in hexane from achiral precursors. In this case the products of the intramolecular cycloaddition were formed in 76% yield and 53% ee,37 strongly suggesting that the metal is still bound to the substrate during the cycloaddition. Nitrone cycloaddition remains a popular synthetic method.New versatile methods for nitrone generation have substantially broadened the scope of this procedure. Nitrones can be generated in high yield by IntermolecularN-alkylation of the sodium salt of an oxime with a chiral epoxide in ethanol.38 IntramolecularN-alkylation of an oxime with a chiral epoxide with ring formation in ethanol at 80 °C.38 Intramolecular addition of an oxime to an unactivated alkene either catalysed by palladium chloride bis-acetonitrile 10 mol% in benzene,39 or mediated by phenylselenyl chloride.40 The nitrones generated by these new methods underwent the normal range of 29 Synthetic methods Part (ii) Pericyclic methods N O CO2Et O O CO2Et H N O CO2Et O CO2Et O N2 N C– O CO2Et O O+ CO2Et N OMe O Bn N2 EtO2C O N O EtO2C O Bn OMe (ii) (i) 52 50 51 49 Oxonium ylide Scheme 18 Reagents (i) Rh(OAc) 2 ; (ii) Rh(O 2 CC 3 F 7 ) 2 N O – R2 R3 N – O R2 R3 N R1 R2 R3 (i) or (ii) 53a R1 = H R2 = CO2Me R3 = H + + 53b R1 = OH R2 = H R3 = OCOPh 54a 55b Scheme 19 Reagents (i) dimethyl dioxirane; (ii) HgO 1,3-dipolar cycloaddition reactions.Dimethyl dioxirane oxidation of proline methyl ester 53a in acetone gave a mixture of cyclic nitrones from which 54a could be easily isolated in 30% yield (Scheme 19).41 Although the yield is poor and the other regio-isomeric nitrone 55a is also produced purification is easy and this method is more attractive than the alternative multistep literature procedure for making this versatile intermediate. Regioselective oxidation of chiral hydroxylamines 53b to nitrone 55b using mercury oxide in methylene chloride was complete within 2 h at room temperature.42 1,3-Dipolar cycloaddition of 55b with dimethyl fumarate in benzene gave after three days at room temperature a 91% yield of cycloadducts as a 4 1 mixture of stereoisomers.The major diastereoisomer was converted to the pyrrolizidine alkaloid ([)-hastanecine. Azomethine ylide cycloadditions remain popular and new innovative methods for generating these species have been forthcoming (Scheme 20). Hence heating homochiral 56 in acetonitrile at 80 °C in the presence of a large range of 30 P. J. Stevenson N+ O CO2PNB CO2H N+ CH– O CO2PNB N S O CO2PNB H Ph Ph N O O O CO2PNB H (ii) (i) 56 57 58 – 59 Scheme 20 Reagents (i) 80 °C MeCN; (ii) Ph 2 CS N SnBu3 Cl N+ CH2 N Ph H (ii) – (i) 62 61 60 Scheme 21 Reagents (i) 110 °C PhMe; (ii) PhCH––CH 2 dipolarophiles in the case shown a thioketone gave racemic cycloaddition products 59 51% yield as a single diastereroisomer.43 Although product 59 is formally derived from the azomethine ylide 57 mechanistic studies suggests that cycloaddition precedes decarboxylation and that azomethine ylide 58 is the true intermediate.44 Azomethine ylide 61 generated by loss of tributyltin chloride from substrate 60 by heating in toluene can be trapped with styrene and gave a 31% yield of cycloadduct 62 as a single stereoisomer (Scheme 21).45 With other dipolarophiles mixtures of stereoisomers resulted.The generality of this procedure is doubtful as all substrates investigated contained a geminal dimethyl group adjacent to the azomethine ylide thus preventing enamine formation.Commercially available trimethylsilyldiazomethane undergoes regioselective 1,3- dipolar cycloaddition with electron deficient chiral disubstituted alkenes in hexane –methylene chloride and gave product 63 containing three new chiral centres as a mixture of diastereoisomers in quantitative yield (Scheme 22).46,47 Removal of the trimethylsilyl group gave 64 exclusively trans in 84% de (with respect to the chirality on the sultam auxiliary) from which 64 could be isolated pure in 71% overall yield for the two steps. Compound 64 is a key intermediate in the synthesis of alkaloid ent-stellettamide. Intramolecular 1,3-dipolar cycloaddition of a thiosemicarbazone 66 was used to construct two rings of the antibiotic palau’amine (Scheme 23).48 Hence condensation of thiosemicarbazide with 65 in acetic acid at 80 °C gave an initial cycloadduct which further condensed and gave the thioimide 67 87–95% yield under the reaction conditions.The reaction is completely regioselective and stereoselective with one chiral centre in the substrate directing the relative stereochemistry of three other centres two of which are tertiary in the product. Tandem [4]2][3]2]-cycloadditions of vinyl nitronates has emerged as a useful protocol for the construction of carbocyclic and heterocyclic compounds (Scheme 24). This reaction sequence is very powerful in that it allows the generation of up to six new chiral centres with control both over the relative and absolute stereochemistry. Permutations of both the [4]2] and [3]2] reactions being inter- or intra-molecular increase the diverse range of structures that can be obtained.Hence intermolecular 31 Synthetic methods Part (ii) Pericyclic methods X OBn O N N SiMe3 X SiMe3 O N N OBn X O N N OBn CO2Et (i) (ii) 63 64 X = Camphor sultam + – Scheme 22 Reagents (i) 25 °C; (ii) ClCO 2 Et AgOTf N N N CO2Me O S H CBz MeO2C N CBz CO2Me N + N – H S H2N MeO2C N CBz CO2Me O (i) 67 66 65 N H Scheme 23 Reagents (i) H 2 NCSNHNH 2 AcOH reflux O N O Me2Si O MeO2C N O O Ph GO O N Ph OG O O N Ph OG O O N Ph OG O O N O OG Ph Ph H2N OH HO O G O N O Me2Si O O MeO2C G Ph (ii) (iv) (iii) (i) or (ii) 75 74 72 71 70 69 68 73 G = detoxinine – – – – – + + + + + Scheme 24 Reagents (i) SnCl 4 ; (ii) methylaluminium bis(2,6-diphenylphenoxide) MAPh; (iii) PhH reflux; (iii) NaBH 4 NiCl 2 [4]2]-cycloaddition of 68 with a chiral enol ether derived from 2-phenylcyclohexan- 1-ol proceeded in methylene chloride at[78 °C in the presence of tin tetrachloride and gave diastereoisomers 69 70 71 in 93% combined yield in the ratio 32 2 1.49 Heating 69 in boiling benzene gave cycloadduct 72 in quantitative yield as a single diastereoisomer.Finally cleavage of the NO bonds followed by reduction gave the tet- 32 P. J. Stevenson N O O Bn O TBSO TBSO N O O Bn O O BnO OBn BnO BnO BnO OBn O OPMB OPMB TEOS TEOS (iii) (ii) (i) 81 80 79 78 77 76 Scheme 25 Reagents (i) 180 °C; (ii) 165 °C; (iii) 45 °C rasubstituted cyclopentane 73 in 82% yield and 94% recovery of the auxiliary. On changing the Lewis acid from tin tetrachloride to MAPh in the initial Diels–Alder reaction the isomer ratio 69 70 71 changed to 1 15 1.8.After intramolecular cycloaddition and ring cleavage of the major diastereoisomer the product is now the enantiomer of 73 i.e. changing the Lewis acid reverses the enantioselectivity for this sequence. Intermolecular [4]2] reaction of chiral vinyl ether with 74 followed by spontaneous intramolecular [3]2] cycloaddition in methylene chloride at [85 °C for 18 h using MAPh as catalyst gave 75 in 59% yield with a de [25 1.50 This was a key intermediate in the synthesis of detoxinine. A similar approach intermolecular [4]2] intramolecular [3]2] was used in the synthesis of mesembrine51 and crotanecine.52 3 Sigmatropic rearrangements Asymmetric aldol reaction of chiral b,c-unsaturated imides with a,b-unsaturated aldehydes gave syn 1,5-dienes 76 in both high de and yield. Protection of the alcohol as a tributylsilyl ether followed by heating in toluene at 180 °C in a sealed tube gave the Cope rearrangement product 77 in 87% yield de [97 3 (Scheme 25).53 As expected the stereochemistry of the two new chiral centres can be controlled by choice of the stereochemistry of the original alkene.Both ends of 77 are suitably di§erentiated to allow further chain extension in either direction. Enol ether 78 derived from glucose undergoes Claisen rearrangement when heated in boiling xylene and gave the eight membered ring product 79 in 60% yield.54 This is the first example of a b-vinyl group on a carbohydrate template undergoing Claisen 33 Synthetic methods Part (ii) Pericyclic methods N N B Ph Ph Br SO2Ar ArO2S R OH R O (i) 84a,b 83 82 a R = OH b R = CO2H Scheme 26 Reagents (i) 1.5 equivalents 83 Et 3 N O OPri O O H2N O OPri O N O OPri N C O O OPri N H O 87 86 85 (ii) (i) Scheme 27 Reagents (i) Bu 3 P CBr 4 Et 3 N[20 °C; (ii) Me 3 Al ring expansion and isomerisation problems of exo going to endo enol ethers were not encountered.Divinylcyclopropane rearrangement of 80 proceeded in tetrahydrofuran at 45 °C for 4 h and gave 81 95% yield with two double bonds at bridgehead positions.55 The first example of an asymmetric aromatic Claisen rearrangement has been reported (Scheme 26).56 Hence 82a rearranges to 84a in 89% yield 94% ee when treated with 1.5 equivalents of chiral boron reagent 83 in methylene chloride at [45 °C containing 1.5 equivalents of triethylamine. The presence of the ortho-hydroxy is important and the ee drops to 57% when this is substituted for a carboxy group 82b.Allyl cyanate to isocyanate rearrangement has been used to introduce stereoselectively nitrogen functionality into a pyran ring (Scheme 27).57 Mild dehydration of primary carbamate 85 to the cyanate proceeded in methylene chloride at[20 °C. On warming to room temperature for one hour the cyanate undergoes [3,3]-sigmatropic rearrangement to isocyanate 86. This was converted in situ to the N-acyl amide 87 by reaction with trimethylaluminium. This one pot sequence produced only the diastereoisomer shown and the overall yield of 87 from 85 was 55%. Deprotonation of chiral amidate 88 in tetrahydrofuran at[78 °C gave keteneN@O acetal 89 which underwent [3,3]-sigmatropic rearrangement on warming to 0 °C and gave 90 in 78% yield 94% de (Scheme 28).58 The valuable auxiliary was easily recovered by hydrolysis of the amide.A catalytic asymmetric allyl imidate to allylic amide [3,3]-sigmatropic rearrangement has been achieved (Scheme 29).59,60 Imidate 91 rearranges to amide 93 in 68% yield 55% ee when heated in methylene chloride at 40 °C containing 5mol% of the chiral cationic palladium catalyst 92. Although the ees in this reaction are still too low for it to be a practical it is a major advance in the search to find a catalytic asymmetric synthesis of acyclic amines. 34 P. J. Stevenson N H Ar O O N Li Ar O ArN MeO (ii) (i) 90 89 88 Ar = Scheme 28 Reagents (i) LDA THF,[78 °C; (ii) 5 h 0 °C then NH 4 Cl N N Cl Pd N N Pd Cl N O Ph p-CF3C6H4 O Ph N p-CF3C6H4 (i) 2+ 91 92 93 2BF4 – Scheme 29 Reagents (i) 5mol% 92 PriO PriO O O PriO PriO O – O – – O PriO PriO O O PriO PriO O – PriO PriO O OH O PriO PriO PriO PriO O OH PriO PriO O OH (iii) (ii) (i) 95 96 94 – – O– Scheme 30 Reagents (i) CH 2 ––CHLi[78 °C; (ii) 0 °C; (iii) NH 4 Cl 0 °C 4 Electrocyclic reactions Diisopropyl squarate reacts with vinyllithiums in tetrahydrofuran at [78 °C to give bicyclo[3.3.0]octane derivative 94 in 45% yield after work up with aqueous ammonium chloride at room temperature (Scheme 30).61 Although the exact details of what is happening are still unclear 94 is formally derived via a 4p-cyclobutene ring opening followed by 8p-electrocyclisation to the eight membered ring followed by an intramolecular aldol condensation on quenching with ammonium chloride.These 35 Synthetic methods Part (ii) Pericyclic methods N OBn OTBS Ar H H N OBn OTBS Ar H Me2PhSi C H SiMe2Ph OTBS N OBn Ar H (ii) 98 97 (i) Scheme 31 Reagents (i) 162 °C; (ii) TBAF SO2Ph H C SO2Ph H O (i) (i) 100 99 S Ph O Scheme 32 Reagents (i) 130 °C pericyclic reactions are clearly accelerated due to the anionic nature of the intermediates.When two moles of cyclopentenyllithium were employed then 96 and 95 containing four fused five membered rings with five contiguous chiral centres were obtained in 40 and 26% yields respectively. The two vinyllithiums need not be the same and when a chiral cyclopentenyllithium was employed as one component then a product containing six contiguous chiral centres was isolated in 49% yield as a single diastereoisomer. 62,63 The complexity of the products derived from such simple starting materials makes this chemistry truly remarkable.5 Ene reactions Intramolecular ene reaction of imine to chiral allene 97 in mesitylene at 162 °C for 2 h gave after removal of the dimethylphenylsilyl group the acetylenic product 98 as a single diastereoisomer in greater than 63% yield (Scheme 31). This intermediate was further elaborated to the alkaloids pancracine64 and coccinine.65 Cyclopentene 100 was formed in 90% yield by heating 99 in o-dichlorobenzene (Scheme 32).66 Tandem [2,3] sulphinate to sulphone rearrangement followed by an intramolecular ene reaction rationalises the formation of 100. Yb(FOD) 3 and acetic acid in the ratio 1 1 0.5 mol% catalyses the ene reaction of methoxypropene (as reagent and solvent) with unactivated aldehydes at 25 °C to give the protected alcohols 101 (Scheme 33).67 For aliphatic and aromatic aldehydes the yields are high and these compounds can be easily hydrolysed to the b-hydroxy ketone.In essence what has been developed is a clean catalytic cross aldol condensation. This chemistry was used as a key step in the synthesis of mitomycinoids68 and phyllanthocin.69 36 P. J. Stevenson R O MeO OMe OMe R O H (i) 101 Scheme 33 Reagents (i) Yb(FOD) 3 References 1 D.A. Evans and J. S. Johnson J. Org. Chem. 1997 62 786. 2 D.A. Evans and D. M. Barnes Tetrahedron Lett. 1997 38 57. 3 D.A. Evans E. A. Shaughnessy and D. M. Barnes Tetrahedron Lett. 1997 38 3193. 4 G. Desimoni G. Faita A. G. Invernizzi and P. Righettil Tetrahedron 1997 53 7671. 5 Z. Zhu and J. H. Espenson J. Am. Chem. Soc. 1997 119 3507. 6 J.D. Winkler H. S. Kim S. Kim K. Ando and K.N. Houk J. Org. Chem. 1997 62 2957. 7 W.R. Roush and D. A. Barda J. Am. Chem. Soc. 1997 119 7402. 8 J.D. Dudones and P. Sampson J. Org. Chem. 1997 62 7508. 9 H. Bienayme and A. Longeau Tetrahedron 1997 53 9637. 10 H. Bienayme Angew. Chem. Int. Ed. Eng. 1997 36 2670. 11 P. Y. Renard Y. Six and J. Y. Lallemand Tetrahedron Lett. 1997 38 6589. 12 M.G. Organ D. D. Winkle and J. Hu§mann J. Org. Chem. 1997 62 5254. 13 K. Endo T. Koike T. Sawaki O. Hayashida H. Masuda and Y. Aoyama J. Am. Chem. Soc. 1997 119 4117. 14 T. S. Powers W. Jiang J. Su W.D. Wul§ B. E. Waltermire and A. L. Rheingold J. Am. Chem. Soc. 1997 119 6438. 15 S. A. Kozmin and V. H. Rawal J. Org. Chem. 1997 62 5252. 16 S. A. Kozmin and V. H. Rawal J. Am. Chem. Soc. 1997 119 7165. 17 D. A. Singleton and Y. K. Lee J. Org. Chem.1997 62 2255. 18 G. J. Bodwell and Z. L. Pi Tetrahedron Lett. 1997 38 309. 19 D. I. MaGee and M. L. Lee Synlett 1997 786. 20 R. J. Stoodley and W. H. Yuen Chem. Commun. 1997 1371. 21 P. T. Perumal and G. Babu Tetrahedron Lett. 1997 38 5025. 22 R. P. C. Cousins W. C. Ding R. G. Pritchard and R. J. Stooley Chem. Commun. 1997 2171. 23 T. Hanamoto H. Furuno Y. Sugimot and J. Inanaga Synlett 1997 79. 24 M.C. Elliot and E. Kruishwijk Chem. Commun. 1997 2311. 25 K. C. Nicolaou M.W. Harter L. Boulton and B. Jandeleit Angew. Chem. Int. Ed. Eng. 1997 36 1194. 26 N. J. Sisti E. Zeller D. S. Grierson and F. W. Fowler J. Org. Chem. 1997 62 2093. 27 I. A. Motorina D. S. Grierson and F. W. Fowler J. Org. Chem. 1997 62 2098. 28 R. Carlini K. Higgs C. Older S. Randhawa and R. Rodrigo J. Org. Chem.1997 62 2330. 29 P. Hsiu and C. C. Liao Chem. Commun. 1997 1085. 30 R. A. Batey D. Lin A. Wong and C. L. S. Hayhoe Tetrahedron Lett. 1997 38 3699. 31 A. Padwa E. A. Curtis and V. P. Sandanayaka J. Org. Chem. 1997 62 1317. 32 T. C. McMorris J. Yu Y. Hu L. A. Estes and M. J. Kelner J. Org. Chem. 1997 62 3015. 33 T. C. McMorris Y. Hu J. Yu and M. J. Kelner Chem. Commun. 1997 315. 34 M.D. Weingarten M. Prein A. T. Price J. P. Snyder and A. Padwa J. Org. Chem. 1997 62 2001. 35 A. Padwa M. A. Brodney J. P. Marino and S. M. Sheehan J. Org. Chem. 1997 62 78. 36 A. Padwa M. A. Brodney J. P. Marino M.H. Osterhout and A. T. Price J. Org. Chem. 1997 62 67. 37 D.M. Hodgson F. Chiappelli N. S. Morrow and A. N. Taylor Tetrahedron Lett. 1997 38 6471. 38 H. A. Dondas M. Frederickson R. Grigg J. Markandu and M.ThorntonPett Tetrahedron 1997 53 14 339. 39 M. Frederickson R. Grigg J. Markandu M. ThorntonPett and R. Redpath Tetrahedron 1997 53 15 051. 40 H. A. Dondas R. Grigg and C. S. Frampton Tetrahedron Lett. 1997 38 5719. 41 M. Closa P. deMarch M. Figuered and J. Font Tetrahedron Asymmetry 1997 8 1031. 42 A. Goti V. Fedi L. Nannelli F. DeSarlo and A. Brandi Synlett 1997 577. 43 D. Planchenault R. Wisedale T. Gallagher and N. J. Hales J. Org. Chem. 1997 62 3438. 44 S. R. Martell P. Planchenault R. Wisedale and T. Gallagher Chem. Commun. 1997 1897. 45 W.H. Pearson and Y. Mi Tetrahedron Lett. 1997 38 5441. 46 G. A. Whitlock and E. M. Carreira J. Org. Chem. 1997 62 7916. 47 M.R. Mish F. M. Guerra and E. M. Carreira J. Am. Chem. Soc. 1997 119 8379. 37 Synthetic methods Part (ii) Pericyclic methods 48 L.E. Overman B. N. Rogers J. E. Tellew and W. C. Trenkle J. Am. Chem. Soc. 1997 119 7159. 49 S. E. Denmark and J. A. Dixon J. Org. Chem. 1997 62 7086. 50 S. E. Denmark A. R. Hurd and H. J. Sacha J. Org. Chem. 1997 62 1668. 51 S. E. Denmark and L. R. Marcin J. Org. Chem. 1997 62 1675. 52 S. E. Denmark and A. Thorarensen J. Am. Chem. Soc. 1997 119 125. 53 M. Rehfeuter and C. Schneider Tetrahedron 1997 53 133. 54 J. Thiem and B. Werschkun Angew. Chem. Int. Ed. Eng. 1997 53 2793. 55 K. C. Nicolaou M.H. D. Postema N. D. Miller and G. Yang Angew. Chem. Int. Ed. Eng. 1997 36 2821. 56 H. Ito A. Sato and T. Taguchi Tetrahedon Lett. 1997 38 4815. 57 Y. Ichikawa M. Osada I. I. Ohtani and M. Isobe J. Chem. Soc. Perkin Trans 1 1997 1449. 58 B. Hungerho§ and P. Metz J.Org. Chem. 1997 62 4442. 59 M. Calter T. K. Hollis L. E. Overman J. Ziller and G. G. Zipp J. Org. Chem. 1997 62 1449. 60 L. E. Overman and T. K. Hollis Tetrahedron Lett. 1997 38 8837. 61 L. A. Paquette and T. M. Morwich J. Am. Chem. Soc. 1997 119 1230. 62 L. A. Paquette A. T. Hamme L. H. Kuo J. Doyon and R. Krenaholz J. Am. Chem. Soc. 1997 119 1242. 63 L. A. Paquette and J. S. Tae Tetrahedron Lett. 1997 38 3151. 64 J. Jin and S. M. Weinreb J. Am. Chem. Soc. 1997 119 2050. 65 J. Jin and S. M. Weinreb J. Am. Chem. Soc. 1997 119 5773. 66 C. Bintzgiudicelli and D. Uguen Tetrahedron Lett. 1997 38 2973. 67 M.A. Ciufolini M. V. Deaton S. R. Zhu and M. Y. Chen Tetrahedron 1997 53 16 299. 68 M.A. Ciufolini M. Y. Chen D. P. Lovett and M.V. Deaton Tetrahedron Lett. 1997 38 4355. 69 M.A. Ciufolini S. Zhu and M.V. Deaton J. Org. Chem. 1997 62 7808. 38 P. J. Stevenson