2 Synthetic methods Part (ii) Pericyclic methods Paul J. Stevenson School of Chemistry The Queen’s University of Belfast Belfast Northern Ireland BT9 5AG 1 Diels–Alder reaction Catalysis The .rst examples of the use of the salen ligand in transition metal catalysed formal Diels—Alder reactions have been independently reported by two groups this year. The metals employed were cobalt(..) and chromium(...) catalysts 1a and 1b respectively (Scheme 1). With 10 mol% of the cobalt catalyst 1a and the activated aldehyde ethyl glyoxalate 2 cycloaddition took place in toluene at 40 °C and gave predominantly the endo stereoisomers 3 and 4 in 90% overall yield. In all the ratio of endo to exo isomers was 93 7 and the Si Re face selectivity was 86 14. When the reaction was performed in the absence of the salen catalyst 1a with diene and aldehyde neat at 60 °C in an autoclave for 4 h then the isomers 3 and 4 only comprised 55% of the reaction mixture with the mass balance 45% comprising the exo isomers.This con.rmed that the chirality already present in the diene was having little in.uence on the stereochemical outcome of the Diels—Alder reaction. The chromium catalyst 1b could be used to promote reactions of aldehydes with the reactive Danishefsky diene. Hence benzaldehyde 5a reacted with Danishefsky’s diene in diethyl ether as solvent at 30 °C containing 2mol% of the chromium salen complex 1b for 24 h to give the cycloadduct 6a in 85% yield and 87% ee. The ee is crucially dependent on the nature of the counterion and tetra.uoroborate was found to be the most e.cient anion.Obviously from a synthetic viewpoint the use of aromatic aldehydes is restrictive. With aliphatic aldehyde 5b and using tert-butyl methyl ether as solvent and 10mol% catalyst 1b cycloaddition proceeded at 30 °C for 24 h to give cycloadduct 6b in high yield and 80% ee. Reduction of the ketone to a secondary alcohol gave a crystalline derivative which was recrystallised to 99% ee. The overall yield for the two steps was 55%. This intermediate was used in a synthesis of muconin. Cationic chiral C symmetric anhydrous copper complexes 7a–d (Scheme 2) and hydrated 7e are .nding further application in Diels—Alder chemistry. An improved procedure for preparing the tert-butyloxazolidine ligand has been published. Complex 7a 10mol% in methylene chloride at room temperature for 18 h catalyses 19 Annu.Rep. Prog. Chem. Sect. B 1999 95 19—38 1a M = Co(II) N N M O But O But But But TBSO CO2Et H TBSO CO2Et O i O O 2 O 3 O O 80% 1b M = Cr(III) counterion tetrafluoroborate CO2Et TBSO O O O 13% 7% exo isomers O H TMSO R ii O 4 O R OMe 6a,b 5a R = Ph 5b R = CH2OPMB Scheme 1 Reagents i toluene 40 °C 10mol% 1a; ii diethyl ether or tert-butyl methyl ether,30 °C 2mol% 1b. Diels—Alder reaction between activated aldehyde ethyl glyoxalate 2 and cyclohexadiene 8 giving cycloadduct 9 in 90% yield. The reaction was completely regioselective the stereoselectivity was very high with only the endo-isomer being detected by NMR spectroscopy and the ee for cycloadduct 9 was 97%.This intermediate was converted to R-actinidolide in four additional synthetic steps. Reaction of carbonyl-activated ketone 10 with Danishefsky’s diene in THF at 78 °C for 20 h in the presence of 0.05mol% catalyst 7b gave cycloadduct 11 in 90% yield and an incredible 98% ee for the newly generated tertiary chiral centre. The catalyst loading is tiny and is approaching enzyme e.ciency in terms of turnover. ,-Unsaturated carbonyl compounds with an additional electron-withdrawing group attached to the carbonyl group usually alkoxycarbonyl or phosphonate are very reactive heterodienes which react with electron-rich alkenes. Hence reaction of diene 12 with ethyl vinyl ether in THF at45 °C in the presence of 10mol% catalyst 7b gave the cycloadduct 13 in high yield and 99% ee. When the reaction was conducted at 78 °C the yield was 89% and the ee increased to 99.7% though the reaction time 50 h was rather long to keep the reaction cold.Copper complex 7e is a blue powder easily stored and is an attractive alternative to the hygroscopic anhydrous complex 7b. Using 2 mol% of catalyst 7e in THF at 0 °C for 0.25 h in the presence of 3Å molecular sieves gave cycloadduct 13 in 87% yield de(endo exo) greater than 24 1 and 97% ee for the endo isomer shown. The ee increases to 99% on dropping the 20 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 7a R = But Counterion SbF 6 – 2+ 7b R = But Counterion TfO– O O 7c R = But Counterion PF 6 – N N Cu R R X X 7d R = Ph Counterion SbF 6 – 7e R = But X = H2O Counterion TfO– 7f R = But X = H2O Counterion SbF6 – O H CO2Et 8 OMe CO2Me TMSO 2 O 10 iii O EtO2C or iv OEt 12 v O EtO2P OEt 14 PhS CO2Et 17 Scheme 2 Reagents i,CH Cl 7a 10 mol% 18 h 25 °C; ii THF,78 °C 0.05mol% 7b 20 h; iii THF 78 °C 10 mol% 7b 50 h; iv THF 0 °C 2mol% 7e 15 min; v CH Cl 78 °C 10mol% 7b 48 h; vi HCl MeOH; vii PPTS acetone—water 4 1; viii CH Cl 78 °C 10 mol% 7d 1 h; ix NaOH (PhO) PON .Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O i H CO2Et 9 ii O O CO2Me 11 OEt O EtO2C 13 vi vii CHO OEt O MeO O EtO2P 15 16 viii ix SPh O CO2Et 18 19 21 temperature to 78 °C.On decreasing the catalyst loading to 0.5mol% the de(endo exo) decreased to 19 1 and the ee to 96%. Heterodiene 14 reacts with ethyl vinyl ether in methylene chloride at78 °C for 48 h in the presence of 10mol% 7b to give cycloadduct 15 in 89% yield. The de for endo exo was 99 1 and the ee was 99%. The nature of the counterion in the catalyst is important in determining the reactivity and enantioselectivity. Hence with catalyst 7c the ee value was lower in reaction of 14 with ethyl vinyl ether. The heterocycle 15 reacted with hydrogen chloride in methanol followed by PPTSin acetone—water to give the ester-aldehyde 16 in 73% yield. Copper complex 7d 10mol% in methylene chloride at 78 °C for one hour catalyses the Diels—Alder reaction of -thioacrylate 17 with cyclopentadiene to give the cycloadduct 18 in 92% yield. The endo exo selectivity was 15 1 and the ee for the endo adduct was greater than 95%.The -thioacrylate 17 is a ketene equivalent and in order to get good ee values in this cycloaddition it seems to be necessary to have two point binding (carbonyl oxygen and sulfur) to the copper catalyst. Hydrolysis of the ester followed by reaction of the carboxylic acid with diphenylphosphoryl azide gave the required ketone 19 in 88% yield and 88% ee. The apparent drop in ee for ketone 19 is due to the presence of the racemic exo-Diels—Alder adduct in the mixture that was hydrolysed. Activated Diels–Alder reactions The activation of dienophiles with electron-withdrawing groups remains popular and this can be enhanced using Lewis acid catalysis.However even with this further activation some dienophiles are still not su.ciently reactive to give clean Diels—Alder reactions with electron-rich dienes so other methods of activation have been sought. One particularly attractive option is to generate a cationic dienophile. Dioxolenium ions have been generated from acetals of ,-unsaturated aldehydes by reaction with silyl tri.ates and these species readily participate in Diels—Alder reactions under very mild conditions (Scheme 3). Hence treatment of diene 20 with dienophile 21 and trimethylsilyl tri.ate in methylene chloride at 90 °C regioselectively gave the endo adduct 22 in 67% yield together with 5% of an unidenti.ed isomer.Of particular note is the use of one quaternary chiral centre in the starting material controlling the stereochemistry of a quaternary centre in the product. The use of cationic dienophiles in intramolecular Diels—Alder reactions has also been reported (Scheme 4). Hence treatment of triene 23 with tri.uoroacetic acid in 2M lithium perchlorate in diethyl ether gave the exo cycloadduct 25 in 66% yield. It is likely that the intermediate for this cycloaddition is the oxygen stabilised carbonium ion 24 and after cycloaddition the intermediate loses its positive charge by proton loss to regenerate the enol ether. Intermediate 25 was used in a synthesis of lycopodine. On the same theme dihydropyridinium ions 27 derived from cyclic amino cyanohydrins 26 readily undergo exo-selective Diels—Alder reaction with Danishefsky’s diene in re.uxing THF containing a catalytic quantity of zinc bromide to give the cycloadduct 28 plus the enone 29 in 66% yield as a 1 1 mixture (Scheme 5). Treatment of this mixture with potassium tert-butoxide in tert-butyl alcohol converted 28 to 29.The dihydropyridinium species 27 is believed to be formed which activates the 22 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 + TBDPSO TBDPSO Scheme 3 Reagents i CH Cl ,90 °C TMSOTf. 22 SPh i 20 HO OTBDPS O OTBS 23 Scheme 4 Reagents i 2MLiClO in Et O 10% CF CO H 1 h. isolated double bond to cycloaddition. In the absence of zinc bromide no reaction was observed.Styrene is unreactive as a diene in Diels—Alder chemistry mainly because cycloaddition involves loss of aromaticity. Very reactive dienophiles or harsh conditions are 25 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O O 21 i O O SPh + OTBDPS O 24 OTBS SPh OTBDPS O OTBS 23 OSiMe3 i + N N CN Bn Bn 27 26 O + OMe N CN N CN 29 28 Bn Bn Scheme 5 Reagents i catalytic ZnBr THF re.ux. 2+ OMe Os(NH3)5 30 i 2+ OMe O ii O Os(NH3)5 OMe O H H 31 Scheme 6 Reagents i 12 equivalents acrolein 1MLiOTf CH CN; ii CAN H O. usually required. However on complexation to pentammineosmium de-aromatises arenes and opens up a whole new range of chemistry for these substrates.Hence -arene—osmium complex 30 reacts with acrolein in molar lithium tri.ate in acetonitrile solution over 12 h at room temperature to give the endo-cycloadduct 31 in 97% yield as a single diastereoisomer (Scheme 6). The osmium can be readily oxidatively removed with ceric ammonium nitrate to give the fully aromatic compounds 32. Imino Diels–Alder reactions The Diels—Alder reaction of dienophiles derived from imines is common. However dienophiles derived from oximes are much rarer. Nitrosation of Meldrum’s acid in the 24 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 OMe 32 OTs N OTs O N O O i or ii O O O O O 33 34 iii N CO2Et 35 Scheme 7 Reagents i benzene 80 °C; ii CH Cl Me AlCl,78 °C 4 h; iii NaOMe then NCS MeOH THF 1 1 overnight.presence of tosyl chloride gave an oxime toluene-p-sulfonate 33 in 57% yield. In thermal Diels—Alder reactions the regioselectivity of dienophile 33 is opposite to that of other imino dienophiles giving adduct 34 in low yield (Scheme 7). The low yield is in part due to the thermal instability of the cycloadduct 34. When the Diels—Alder reaction was conducted in methylene chloride at78 °C mediated by two equivalents of dimethylaluminium chloride 34 was obtained in 78% yield. The cycloadduct 34 can be readily converted to 2-methoxycarbonyl pyridines by elimination of the toluene-psulfonate and decarboxylation of the one of the esters. The overall yield for this pyridine synthesis is 57% from 33.Intramolecular Diels–Alder reactions When a 1Msolution of the polyene 36 was heated in toluene at 120 °C in the presence of dienophile 37 an exo-selective intramolecular and an exo-selective intermolecular Diels—Alder reaction took place giving 38 in 45% yield (Scheme 8). In one pot six new chiral centres were generated with the correct absolute stereochemistry for elaboration to ()-chlorothricolide. Taking into account all possible exo endo and regiochemical possibilities for these diene—dienophile combinations 96 di.erent Diels—Alder products are possible; the yield of 45% is therefore excellent. Intramolecular Diels—Alder reaction of substrate 39 has been used to simultaneously construct a six-membered ring and a macrocycle in the synthesis of pinnatoxin A (Scheme 9). There are eight possible products from the cyclisation but only three were formed.It was found that the choice of solvent in which the reaction was carried out had an e.ect on the relative amounts of these isomers. Dodecane proved to be the best solvent and heating a 0.2mM solution of 39 at 70 °C for 24 h gave a 78% combined yield of cycloadducts in the ratio of 1 0.9 0.4 of which the major exo-isomer 40 shown was the desired one. 25 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 OTBDPS OTBDPS O O O O O i O But But CO2R CO2R 37 38 36 OMOM OMOM Scheme 8 Reagents i 1.0Min toluene 120 °C. Scheme 9 Reagents i 0.2mM in dodecane 70 °C 24 h. Intramolecular Diels—Alder reaction of unactivated alkynes with dienes usually requires high temperatures.Cationic rhodium complex 41 6mol% in methylene chloride at room temperature for 14 h catalyses the formal intramolecular Diels—Alder reaction giving the adduct 42 in 65% yield as a single diastereoisomer (Scheme 10). The reaction also works for alkene dienophiles but isomerisation to the enol ether is a 26 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 Scheme 10 Reagents i CH Cl 25 °C 14 h 6mol% 41. side reaction. It is doubtful if this process is concerted but nevertheless the synthetic potential of these reactions has yet to be realised. 2 1,3-Dipolar cycloadditions Azomethine ylides Chiral azomethines 43 are generated by treating the corresponding secondary amine with aldehydes in boiling toluene.These species undergo regio- and stereoselective 1,3-dipolar cycloadditions with both imines and aldehydes (Scheme 11); for example the cycloadducts 44 and 46 were obtained in yields of 43 and 53% respectively as single diastereoisomers. In the chiral aldehyde case it is believed that the contributions to asymmetric induction from the chiral 1,3-dipole and chiral aldehyde are matched. Hydrogenolysis of the benzylic amines followed by hydrolysis of theN,Oand O,O-acetals gave the vicinal diamines 45 and vicinal amino alcohols 47 in yields of 83 and 95% respectively. This constitutes a very e.cient and elegant synthesis of polyoxamic acid 47. It has been demonstrated that unstabilised cyclic azomethine ylides 49 can be generated by treating 2,5-bis(trimethylsilyl) pyrrolidines 48 with two equivalents of silver .uoride in methylene chloride (Scheme 12). These transient species rapidly undergo 1,3-dipolar cycloaddition with methyl (E)-3-(6-chloro-3-pyridyl)prop-2- enoate giving mixtures of endo and exo stereoisomers 51 and 50 ratio 1 3 in 80% combined yield.The desired isomer was 51 but unfortunately the reaction was exoselective. Use of the corresponding cis-alkene gave a 62% yield of the exo-isomer in which the aryl group was equatorial. This intermediate has been converted to epibatidine. Intramolecular 1,3-dipolar cycloaddition of an azomethine ylide 53 has recently been employed as a key step in the synthesis of the tricyclic core of sarain A (Scheme 13). Hence heating amine 52 in boiling toluene containing paraformaldehyde gave 54 27 Annu.Rep. Prog. Chem. Sect. B 1999 95 19—38 Bn Bn N R N NH Ar 2 R N Ar Ph CO2H ii i Ar Ph N+ iii – NH2 44 O O O O R O 43 OH iv ii N Ph O CO2H HO O O iii OH NH2 O CHO O O 47 Pd(OH) ; iii HCl CH OH; iv 46 Scheme 11 Reagents i PTSA toluene 110 °C; ii H toluene 110 °C with H O removal. i – + N N TMS TMS Bn Bn N 49 48 Cl Bn Bn N Ar 45 CO2Et CO2Et EtO2C N Ar 50 51 Scheme 12 Reagents i 2 equivalents AgF CH Cl . in 97% yield presumably via the stabilised azomethine ylide 53. Three new chiral centres with the correct relative stereochemistry were established in one step. The yield dropped to 78% when the reaction was scaled to 7 g.Aza allyl anions Aza allyl anions are readily generated by treating the corresponding -stannyl imine with n-butyllithium at low temperature. These species undergo a variety of anionic cycloaddition reactions. Hence treatment of 55 with n-butyllithium in THF at78 °C gave aza allyl anion 56 which underwent intramolecular anionic cycloaddition and gave 57 in 45% yield as a single stereoisomer after an aqueous work up Scheme 14. The chirality at the protected secondary alcohols controls the absolute stereochemis- 28 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O CO2Et O CO2Et H NH2 i Bn N N + Bn N – OBn 52 OBn 53 O CO2Et H N Bn N H OBn 54 O) toluene 110 °C. Scheme 13 Reagents i (CH Scheme 14 Reagents i 4 equivalents n-BuLi THF,78 °C 2 h; ii H O.try at the three newly formed chiral centres in this concerted cycloaddition. Intermediate 57 was converted to coccinine. Nitrile ylides 60 in which the alkyl substituent R is not phenyl are rare. Recently synthetic equivalents to these species have been developed from heteroatom substituted 2-aza-allyl anions 59 Scheme 15. Hence when substrates 58a–c were treated with n-butyllithium in THF at 78 °C in the presence of an electron-rich dipolarophile in this case vinyltriethylsilane cycloaddition took place initially giving 61 followed by elimination of the heteroatom as the corresponding anion to give 62. Three di.erent heteroatoms oxygen nitrogen and sulfur were studied and oxygen gave the best yield of 62 97%.Normally nitrile ylides 60 react with electron-poor alkenes so these two methods to some extent complement each other. The chemistry can also be applied to cyclic systems 63 but in these cases the heteroatom cannot eliminate for geometric reasons. This chemistry gives rapid access to the biologically important azabicyclo[3.2.1]octane skeleton 64 in 90% yield. 29 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 Scheme 15 Reagents i THF,78 °C BuLi. Ph O O i S S N Ph + N S S O O– O O 66 65 86% yield Scheme 16 Reagents i CH 67 Cl 25 °C. Nitrone cycloadditions The use of chiral C symmetric dipolarophile 66 in reactions with nitrones 65 has the advantage that the products arising from both the exo and endo transition states are identical.This drastically reduces the number of possible stereoisomeric products that can be formed. Hence reaction of 66 with 65 in dichloromethane at room temperature gave adduct 67 in 86% yield as a single diastereoisomer Scheme 16. Full experimental details on the preparation of dipolarophile dienophile 66 have recently been published. Catalytic asymmetric 1,3-dipolar cycloaddition of nitrones 68 to achiral ,-unsaturated imides derived from oxazolidinones 69 has been achieved Scheme 17. The catalyst is derived from binol ytterbium tri.ate and to get good enantioselectivity it is crucial to add 2 mol of amine shown per mol of catalyst. At present the catalyst loading is heavy 20 mol% but the results are remarkable.Nitrone 68 reacts with 69 in methylene chloride containing molecular sieves type 4Å and 20mol% of catalyst to give cycloadduct 70 in 92% yield. The endo exo selectivity for the cycloaddition is greater than 99:1 and the ee is 96%. Aza-C-disaccharides are emerging as new selective glycosidase inhibitors. A con- 30 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 + Yb(OTf)3 + N 2 O O O – i Bn +N N Ph 69 68 Scheme 17 Reagents i 20mol% ytterbium catalyst 4Å molecular sieves CH Cl 70 O 25 °C 5 h. AcO O + O– OAc 71 i or ii AcO O OAc Scheme 18 Reagents i toluene 110 °C; ii toluene 60 °C 10 kBar. venient entry to this class of compound involves 1,3-dipolar cycloaddition of cyclic nitrones 72 with carbohydrate derived enol ethers 71 followed by cleavage of the NO sigma bond Scheme 18. The cycloadditions are completely regioselective giving only the isomer 73 shown.73 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 OH OH Catalyst O Bn N O Ph N O O OBut OBut N + 72 OBut OBut N O 31 COMe MeCO N2 EtO2C O – 2C R R + O i MeO2C EtO MeO2C O OTBDPS O OTBDPS OTMS OTMS 74 75 MeCO COMe EtO2C R O MeO2C O OTBDPS OTMS 76 Scheme 19 Reagents i 5mol% Rh (OAc) benzene 80 °C. The absolute stereochemistry is governed by the substituent on C3 on the glycal and C2 of the nitrone and in the case shown both are ‘matched’. With the purely thermal reaction the yield is 68% but when high pressure is applied the yield increases to 100%.Oxonium ylides Oxonium ylides are readily generated by reaction of carbenes derived from diazo compounds with carbonyl groups. To ensure good chemoselectivity ylide generation is usually intramolecular. Hence treatment of diazo compound 74 with 5mol% rhodium acetate in boiling benzene gave the transient oxonium ylide 75 which underwent 1,3-dipolar cycloaddition with electron-de.cient hex-3-ene-2,5-dione to give 76 in 47% overall yield. Substrate 76 contains the basic carbon skeleton of zaragozic acid Scheme 19. Trimethylene methanes Trimethylene methanes 78 are readily generated by heating an appropriately substituted vinyl cyclopropane 77 Scheme 20. These species behave as 1,3-dipoles and add to electron-de.cient O-benzyl oximes to give pyrrolidines 80 in good yield.Hence heating a neat mixture of 77 and 79 at 80 °C for 1.5 h gave 80 in 79% yield. Acetonitrile may be used as a solvent in these reactions. The vinyl acetals can be hydrolysed to give ester functionality. This represents one of the few dipolar cycloaddition methods for forming pyrrolidines in which the dipolarophile contains nitrogen. 3 22 Cycloadditions 22 Cycloadditions of stable trimethylsilyl ketenes with aldehydes have been used in the synthesis of the -lactone-containing natural products the panclinins Scheme 32 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 i O O O O O O + – + – 78 BnO N i CO2Me 79 O O N BnO CO2Me 80 Scheme 20 Reagents i 80 °C neat.O O TBSO 77 O TBSO O C i R H R1 R Me R1 3Si SiMe3 83 R1 = (CH2)6CH3 R = (CH2)7CH(CH3)2 + 81 82 O TBSO O SiMe3 R1 R 84 84% combined yield Scheme 21 Reagents i Et AlCl Et O,40—0 °C. 21. The cycloadditions are completely regioselective giving only -lactones as cis—trans mixtures of diastereoisomers. The absolute stereochemistry of the cycloaddition is controlled by the remote tributylsilyl protected secondary alcohol. Hence reaction of ketene 82 with aldehyde 81 in diethyl ether at40 to 0 °C in the presence of diethylaluminium chloride gave 83 and 84 in 84% combined yield and in the ratio of 4.9 1. Carbon desilylation was readily achieved using tetrabutylammonium chloride in THF at 90 °C and gave predominantly the trans-disubstituted -lactone which could be crystallised to isomeric purity.Photochemical Paterno—Buchi 22 cycloaddition of aromatic aldehydes with 33 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O O O i R R R N H Ph N N Ph Ph CO2Me 85 CO2Me CO2Me 86 Ph R N CO2Me O i N N Bn Bn N 90 89 87 ii HO O O O N N Bn Bn 88 Scheme 22 Reagents i h CH CN; ii H Pd/C. N N N 91 ii O N Bn N 92 Scheme 23 Reagents i h CH CN 1 h; ii HOAc pyridine CH CN 3 h re.ux. cyclic enamides has been used to prepare trisubstituted pyrrolidines regioselectively and with reasonable stereocontrol Scheme 22. Hence irradiation of benzaldehyde and cyclic enamide 85 in acetonitrile gave 86 and 87 in 65% combined yield ratio 1 4.4.Catalytic hydrogenolysis of the benzylic ether 87 gave 88 an intermediate in the synthesis of preussin. The central core of the manzamine alkaloids was rapidly constructed by a 22- 34 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 Bu3Sn Bu3Sn i N N Ph BOC BOC H 94 Ph 93 Scheme 24 Reagents i 1.3 equiv. LDA THF—HMPA ratio 4 1 78 to 40 °C 20 h. – TfO S + S H i Me 95 96 Scheme 25 Reagents i LDA THF—N,N-dimethylpropylene urea 4 1,78 °C. photo-induced intramolecular cycloaddition of vinylogous amide with an alkene Scheme 23. Hence irradiation of 89 in acetonitrile for 1 h gave an unstable strained adduct 90 not isolated which underwent retro-Mannich reaction followed by cyclisation to give 91.Treatment of adduct 91 with pyridinium acetate in boiling acetonitrile gave the Mannich cyclisation product 92 in 58% overall yield from 89. 4 Sigmatropic rearrangements The 2,3-Wittig rearrangement has seen widespread usage in synthesis. However the aza version of this reaction is more di.cult and is usually only observed when there is substantial release of ring strain. The reasons for this are largely due to the fact that nitrogen is less electronegative than oxygen. However recently examples of this process have being appearing. The use of vinyl stannanes in this reaction helps give useful stereocontrol Scheme 24. Treatment of 93 with LDA in THF—HMPA 4 1 at 78 °C and then allowing to warm to 40 °C gives the aza-Wittig rearrangement product 94 in 71% yield as a single diastereoisomer.Since the tributyltin moiety can be replaced with a plethora of other functionalities this is synthetically a very useful group for directing the stereochemical outcome of a reaction. Thia Sommelet—Hauser rearrangement of sulfonium salt 95 takes place when it is treated with LDA in a solvent mixture of THF andN,N-dimethylpropylene urea ratio 4 1 to give 96 in 87% yield Scheme 25. What makes this reaction very special is that a quaternary chiral centre is generated with de 90% and the aromaticity of the ring is lost. 3,3-Sigmatropic rearrangements usually proceed at reasonably high temperatures. There have been numerous reports of anion accelerated 3,3-sigmatropic rearrangements.The .rst example of a radical accelerated rearrangement has now been reported Scheme 26. Treatment of substrate 97 with tributyltin hydride and a catalytic quantity of AIBN in re.uxing benzene gives the rearranged product 98 in 74% yield. A 35 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 • Bu3Sn Bu3Sn O Bu3Sn O O O O O [3,3] • • 97 Bu3Sn Bu3Sn H O O H CO2Et O OH i H 99 CO2Et 98 Scheme 26 Reagents tributyltin hydride catalytic AIBN benzene 80 °C. 90% yield 97% ee 2 CO2Et O BnO ii BnO OH H CO2Et 101 2 O iii H CO2Et 2 62% yield 98% ee CO2Et OH 100 Cl 0 °C. 102 Scheme 27 Reagents i 1mol% 7f CH Cl 0 °C 6 h; ii 1mol% 7f CH Cl 25 °C; iii 10mol% 7a CH possible mechanism is outlined in Scheme 26 though of course it is possible to draw other non-concerted pathways.5 Ene reactions Chiral Lewis acid 7f catalyses the ene reaction of a variety of alkenes with ethyl glyoxalate 2 Scheme 27. Hence treatment of methylenecyclohexane with aldehyde 2 in the presence of catalyst 7f 1 mol% in methylene chloride at 0 °C gave adduct 99 in 90% yield 97% ee. Good regioselectivity is observed for unsymmetrical alkenes. Hence reaction of alkene 100 with aldehyde 2 in methylene chloride at room temperature containing 1mol% 7f gave adduct 101 in 62% yield with ee 98%. Examples of 1,2-disubstituted alkenes are also reported. Hence treatment of cyclohexene with aldehyde 2 in methylene chloride at 0 °C in the presence of catalyst 7a 10 mol% gave 102 ratio endo exo 86 14 in 96% yield and 96% ee for the endo isomer shown.36 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 O EtO N Scheme 28 Reagents i benzotri.uoride 5mol% 104 room temperature. 105 103 Me3Si Scheme 29 Reagents i toluene 110 °C 3 h. Previously reported ene reactions of 1,2-disubstituted alkenes were never catalytic in Lewis acid so this is a major advance in this area. Given the versatility of these copper catalysts it is remarkable that the reactions show such high chemoselectivities. Chiral Lewis acid catalysed ene reactions of electron-de.cient imines 103 with alkenes have also been employed for amino acid synthesis Scheme 28. Treatment of electron-de.cient 103 with 2-phenylprop-1-ene in the presence of 5mol% copper catalyst 104 in the unusual solvent benzotri.uoride at room temperature gave adduct 105 in 55% yield and 99% ee.The yield increased to 92% when two mol of alkene were employed. The N-tosyl group and ester groups were hydrolysed with hydrogen bromide in phenol. Under these conditions no racemisation or double bond isomerisation was observed. c X = SiEt3 yield 20% 2+ Tol2 N P Cu H P N Ph Tol2 Ts 2ClO4 – 104 i O Ph EtO N H Ts O O O O i OH OH Me3Si X X 106 107 a X = SnBu3 yield 90% b X = H yield 54% 37 Annu. Rep. Prog. Chem. Sect. B 1999 95 19—38 6Electrocyclisations Heating trienes 106a–c in boiling toluene results in stereoselective electrocyclisation to give 107a–c Scheme 28. The yield is critically dependent on the nature of X with the best yield being obtained when XSnBu 107a 90%.It has been postulated that there is an attractive interaction between the tributyltin moiety and the secondary alcohol and this holds the molecule in the correct conformation for electrocyclisation however the silyl group and the oxygen group repel each other hence the low yield when XSiEt . References 1 Y. J. Hu X. D. Huang Z. J Yao and Y. L. Wu J. Org. Chem. 1998 63 2456. 2 S.E. Schaus J. Branalt and E. N. Jacobsen J. Org. Chem. 1998 63 403. 3 S.E. Schaus J. Branalt and E. N. Jacobsen J. Org. Chem. 1998 63 4876. 4 D.A. Evans G. S. Peterson J.S. Johnson D. M. Barnes K. R. Campos and K. A. Woerpel J. Org. Chem. 1998 63 4541. 5 S.L. Yao M. Johannsen R. G. Hazell and K. A. Jorgensen J. Org. Chem. 1998 63 118. 6 S.L. Yao M. 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