Cycloaddition of Oxidopyrylium Species in Organic Synthesis

Cycloaddition of oxidopyrylium species in organic synthesis

Vishwakarma Singh*, Urlam Murali Krishna, Vikrant, Girish K. Trivedi*

Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India

Contents

1. Introduction ...... 3405 2. Generation and cycloaddition of oxidopyrylium species from epoxyindanones ...... 3406 2.1. Intermolecular cycloadditions ...... 3406 2.2. Intramolecular cycloadditions ...... 3407 3. Generation and cycloaddition of oxidopyrylium species from acetoxypyranones (pyranulose acetates) ...... 3407 3.1. Intermolecular cycloadditions ...... 3407 3.2. Intramolecular cycloadditions ...... 3410 3.3. Asymmetric cycloadditions ...... 3411 4. Oxidopyrylium species from b-hydroxy-g-pyrones and their cycloadditions ...... 3412 4.1. Intramolecular cycloadditions ...... 3412 4.2. Intermolecular cycloadditions ...... 3413 4.3. Asymmetric cycloadditions ...... 3414 5. Cycloaddition of oxidopyrylium species (from acetoxypyranones and/or b-hydroxy-g-pyranones) in the synthesis of natural products ...... 3415 6. Tandem [5þ2] cycloaddition of oxidopyrylium species and [4þ2] cycloadditions ...... 3420 7. Transformation of dimer of 3-oxidopyrylium ...... 3420 8. Rhodium-catalyzed generation of carbonyl ylides and their cycloadditions ...... 3421 9. Concluding remarks ...... 3425 Acknowledgements ...... 3425 References and notes ...... 3425 Biographical sketch ...... 3428

1. Introduction complexity in a stereocontrolled manner are some of the important aspects of organic synthesis.1 Cycloaddition reactions, The development of efﬁcient methodology and the discov- which allow two new bonds to be formed in one operation in ery of new processes for the rapid creation of molecular a regio- and stereocontrolled fashion, occupy a central position

Abbreviations: Ac, Acetyl; acac, acetylacetonyl; Bn, benzyl; Bz, benzoyl; COD, cycloocta-1,5-diene; Cp, cyclopentadienyl; m-CPBA, m-chloroperbenzoic acid; Cy, cyclohexyl; DBN, 1,5-diazabicyclo[4.3.0]non-5-ene; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAD, dimethyl acetylenedicarboxylate; DMAP, 4-di- methylaminopyridine; DME, ethylene glycol dimethyl ether; DMF, N,N-dimethylformamide; ee, enantiomeric excess; HMPA, hexamethylphoramide; LDA, lith- ium diisopropylamide; Ms, methanesulfonyl; MOM, methoxymethyl; NBS, N-bromosuccinimide; NMO, 4-methyl morpholine N-oxide; PCC, pyridinium chlorochromate; PMB, p-methoxybenzyl; PMP, p-methoxyphenyl; Py, pyridine; PTC, phase transfer catalyst; TBAF, tetra-n-butylammonium fluoride; TBS, tert-butyl dimethylsilyl; TBDPS, tert-butyldiphenylsilyl; TBSOTf, tert-butyldimethylsilyltriflate; Tf, trifluoromethanesulfonate; TIPS, triisopropylsilyl; TMP, tetramethylpiperidide; TMS, trimethylsilyl; TMSOTf, trimethylsilyltriflate; p-Tol, p-tolyl; Ts, p-toluenesulfonyl. 3406 among the available tools of synthetic organic chemistry. the endo isomer and furnished the adducts 14, 15 and 17, 18, Among the various types of cycloadditions, dipolar cycloaddi- respectively (Scheme 3). tions of oxidopyrylium species of the types IeIII (Fig. 1) and the related carbonyl ylides have proved to be a powerful meth- - odology for the synthesis of diverse molecular architectures, O O Ph Ph O which are not readily available otherwise. The intention of Ph Δ or hν O this review is to discuss the developments in the chemistry O O+ 1 Ph 2 of oxidopyrylium species reported in the literature to date. Ph Ph Previously, there have been a few reviews that have appeared 3 MeO C CO Me in the literature, but in most cases, these have dealt with differ- 2 2 2e5 Ph ent perspectives. We wish, in the current survey, to high- COOMe light the cycloaddition of oxidopyrylium ylides and their O O application in organic synthesis. Cycloaddition of the related COOMe carbonyl ylides, generated by rhodium-catalyzed addition of Ph diazo ketones, has recently been reviewed6,7 and hence, only 4 the recent developments are covered here. It is believed that Scheme 1. such an overview will give a better understanding of the subject to the reader and will, hopefully, stimulate further investigation. O Ph X O O O H O O Ph 5a O , X = O X - 5b H O - - 1 , X = NPh Ph O O Ph O Ar OR Δ or 8, X = O (89%) hν 9, X = NPh (93%) O+ O+ O+ O O- RCN Ph I Ar II III Ph O CN 6a, R = H Figure 1. Oxidopyrylium species. O+ 6b, R = Me R 2 Ph Ph 10, R = H (98%) 11, R = Me (80%) 2. Generation and cycloaddition of oxidopyrylium species O Ph Cl Cl from epoxyindanones O Cl 7 2.1. Intermolecular cycloadditions Cl Ph 12 (72%)

Ullman and co-workers have reported that 2,3-diphenylin- Scheme 2. denone oxide 1, upon thermolysis or photolysis, produces the red-coloured benzopyrylium oxide 2.8 The benzopyrylium oxide 2 behaves as a carbonyl ylide and undergoes cycload- O O O Ph Ph ditions with alkenes such as norbornadiene and dimethyl ace- H H Δ or hν Ph O O tylenedicarboxylate to produce the cycloadducts 3 and 4, O O + O O O respectively (Scheme 1). Irradiation of 2,3-epoxy-2-methyl- O O 1 Ph O H O O Ph H Ph 3-phenylindanone in the presence of dimethyl acetylenedi- 13 3:1 carboxylate was also found to give an adduct.9 Later, Lown 87% 14 15 and Matsumoto extensively studied the cycloaddition of Ph O H benzopyrylium oxide 2 with various dipolarophiles.10 They O Δ ν O 18 observed that the cis 2p-addends underwent cycloadditions Ph or h + (exo) + O 93% with the benzopyrylium ion 2 to give a mixture of endo PhH 1 Ph 3:2 and exo adducts in which the formation of the endo adducts 16 17 predominated. Scheme 3. The benzopyrylium ylide 2 reacted with alkenes such as maleic anhydride 5a and N-phenyl maleimide 5b and provided exclusively the endo adducts 8 and 9, respectively. Similarly, cycloaddition with cis-alkenes 6a,b gave the adducts 10 and In contrast to the above observations, the cycloaddition of 11, respectively, and 7 also resulted in the formation of the benzopyrylium oxide 2 with cis-stilbene 19 and dimethyl endo adduct 12 (Scheme 2). The alkenes 13 and 16, however, maleate 20 gave a mixture of adducts 21e24 having the exo gave a mixture of endo and exo isomers with a preference for adducts as the major products (Scheme 4). 3407

O O Ph O Ph O Ph Ph Ph Ph Δ ν Ph 19 O Ph O Ph or h O + Ph + O O O 72% Ph O Ph Ph Ph 1 Ph Ph 40 Ph Ph 21 Δ ν 22 41 Ph or h 1:3.6 R1 O Δ O Ph O Ph -CO 1 Ph 94% O Ph O O Ph O CO2Me + CO2Me R2 O R1 CO2Me CO2Me O Ph MeO2C CO2Me Ph Ph 20 23 1:3.6 24 R Ph 2 Ph Ph 43a 42 Scheme 4. , R1 = R2 = COPh (92%) 43b , R1 = Ph, R2 = COOMe (86%) 43c , R1= Ph, R2 = H (82%) e The trans 2p-addends 25 29 also gave a mixture of ad- Scheme 5. ducts 30e39 in which a tendency to form the 2-exo-3-endo isomer is observed (Table 1). With very bulky substituents O such as benzoyl on the addend (entry 5), the exclusive forma- O Ph Δ ν tion of the 2-exo-3-endo isomer was observed. Diphenyl- Ph or h O Bu-t + P Bu-t cyclopropenone 40 underwent cycloaddition with 2 to give O P 44 the cycloadduct 41, which subsequently loses carbon mon- 1 Ph 45 Ph oxide to produce the adduct 42. The adduct 42 was also Scheme 6. obtained directly by the addition of diphenylacetylene to the 10 11a ylide 2 (Scheme 5). George and his associates also 2.2. Intramolecular cycloadditions prepared adducts 43aec by thermal activation of the epoxide 1 in the presence of various acetylenic dienophiles Feldman has reported the intramolecular counterparts of the (Scheme 5). aforementioned cycloaddition.12 Irradiation of the mono- Very recently, Regitz and co-workers reported that unusual substituted epoxyindenones 46 and 48 having oleﬁnic tethers dipolarophiles such as the phospha alkyne 44 also underwent gave the cycloadducts 47 and 49 (Scheme 7). Irradiation of regiospeciﬁc cycloaddition to provide an oxa-bridged phospha 11b 48 also produced the product 50, in an equal amount, which alkene derivative 45 (Scheme 6). is apparently formed via the intermediates 51 and 52.12

O O Me hν, 300 nm Table 1 O PhH Cycloaddition of benzopyrylium species derived from 1 with various O Pyrex Me dienophiles 4665% 47 O O O O Ph O Ph O R Δ ν hν, 300 nm Ph or h O O + R O R O PhH Me + O R + O R Pyrex 1 Ph R 48 Me 49 50 Ph Ph 34% Me 25, R = Cl 30, R = Cl 35, R = Cl 36 26, R = CN 31, R = CN , R = CN [2+2] 27, R = Ph 32, R = Ph 37, R = Ph 28 33 38, R = CO Me O , R = CO2Me , R = CO2Me 2 O 29, R = PhCO 34, R = PhCO 39, R = PhCO . . O O Entry Dipolarophile Products Ratio Yield (%) 51 Me 52 Me Cl 1 30/35 4:1 69 Cl Scheme 7. CN 2 31/36 7:1 85 NC Ph 3 32/37 5:2 93 3. Generation and cycloaddition of oxidopyrylium species Ph from acetoxypyranones (pyranulose acetates) COOMe 4 33/38 3:1 92 MeOOC 3.1. Intermolecular cycloadditions

COPh 5 34/39 d 88 Achamatowicz and co-workers have reported an interesting PhOC method for converting furan derivatives into pyranones. 3408

2-Furylcarbinols such as 53 on treatment with bromine in ethyl vinyl ether 69, norbornadiene 72, and norbornene 73 methanol yielded the acetals 54 as a mixture of epimers. reacted with 3-oxidopyrylium to produce the corresponding Mild acid hydrolysis of 54 produced the hydroxypyranones cycloadducts (Scheme 10).19,20a The cycloaddition of oxido- 55 (Scheme 8).13 This whole process is now known as the pyrylium species derived from pyranulose acetates 57 and 67 Achamatowicz rearrangement and provides interesting build- gave single endo adducts 70 and 71, respectively. In the case ing blocks for the synthesis of a large number of polyoxygen- of norbornadiene and norbornene, ‘exo-syn’ adducts 74e76 ated natural products from simple furan derivatives.14e16 were obtained. Interestingly, the reaction of 58 with 2,3-dime- Hendrickson and Farina reported that the acetoxypyranone thylbutadiene gave the unusual adduct 77.19 57, which can be obtained by the acetylation of pyranone 56, can serve as potentially versatile source of carbonyl ylides. O O- R OEt O The acetoxypyranone 57 on exposure to either heat or a tertiary R R base 69 base, such as triethylamine, generates the carbonyl ylide 58 O O O+ 72 formulated as 3-oxidopyrylium. The ylide 58 is a reactive spe- OEt OAc 70, R = H (56%) 58, R = H cies and can be trapped with suitable dipolarophiles such as 57, R = H 71, R = Me (47%) 68, R = Me DMAD to furnish the corresponding cycloadduct 59.17 67, R = Me 73 O Br R1 2 R O- R MeO R O H O H R1 MeOH 2 R Me O R1 O OMe O 72 73 R2 OH O O R2 OH O O+ 53 OH 54 55 O Me R = R = H H 58 H 77 1 2 , R = H 75, R = H (63%) 74, R = H (50%) 68 R1 = CH2OH, R2 = H , R = Me 76, R = Me (67%) R1 = Me, R2 = H R1 = R2 = CH2OAc Scheme 10.

O O O- O Sammes and co-workers reported that 2-substituted pyr- Ac2O Δ or DMAD COOMe O ylium ions such as 2-methyl-3-oxidopyrylium 68 and 2-phe- O Py O base O+ 42% COOMe nyl-3-oxidopyrylium 79 on cycloaddition with substituted OH OAc dipolarophiles furnish the cycloadducts having a reverse regio- 56 57 58 59 chemistry from that observed with the unsubstituted 3-oxido- Scheme 8. pyrylium (Table 2). For instance, the cycloaddition of acrylonitrile with 3-oxidopyrylium 58 gave a single isomer Hendrickson and Farina also reported that 3-oxidopyrylium 80 (35%), while the reaction of acrylonitrile with 2-methyl- reacted sluggishly with maleic anhydride 5a and sulfone 60 to 3-oxidopyrylium 68 gave a mixture of three isomers (81e give the adducts 62e64. Acrolein 61 reacted with 58 with 83) in approximately equal amounts. Similarly, the reaction greater efficiency and furnished the adducts 65 and 66 of 58 with styrene gave a single adduct 85 (65%), whereas (Scheme 9). They also observed that the regioselectivity was the oxidopyrylium 79, derived from 78, reacted with styrene as anticipated. The stereoselectivity, however, which favours 84 gave a mixture of three products 86e88 in a 1:6:3 ratio.20b 18 the formation of the exo adduct, is in contrast to Alder’s rule. Sammes and Street rationalized the formation of reverse re- O O gioisomers (i.e., C-7) in the cycloaddition of unsymmetrical O O O O O O + O dipolarophiles to 3-oxidopyrylium by invoking frontier molec- O O 20b 5a ular orbital (FMO) theory. Table 3 summarizes some addi- O O 62 63 e 3:1 tional examples of the adducts 89 109 obtained by O O - cycloaddition of various oxidopyrylium species and a variety SO2C4F9 O Δ or of dipolarophiles. O O base O + 60 Mascarenas and co-workers reported a highly efficient cy- SO2C4F9 cloaddition between the oxidopyrylium derived from 57 and OAc 35% 64 57 58 the cyclopropenone acetal 110, which gave the adduct 111 23a CHO O O in excellent yield (Scheme 11). Further transformation of + O O 61 the adduct was also reported (vide infra). Aggarwal and co- CHO CHO 23b 69% workers examined the cycloaddition of 112 with the oxido- 65 66 4:1 pyrylium species generated from 57, which gave a mixture of Scheme 9. three adducts 113aec (Scheme 11). Recently, Radhakrishnan24 and co-workers reported a Sammes and co-workers subsequently reported the intermo- highly interesting and novel dipolar cycloaddition of pentaful- lecular trapping reactions of 3-oxidopyrylium with a range of venes with 3-oxidopyrylium betaines, in which the formation electron-rich and electron-deficient olefins and thus greatly ex- of eight-membered ring systems was observed. Thus, the reac- tended the utility of the 3-oxidopyrylium ylides.19,20 Thus, tion of pyranulose acetates 57 and 67 with a variety 3409

Table 2 Cycloaddition of 2-substituted oxidopyrylium species with acrylonitrile and styrene O O O CN R 6a R O O R O O O- CN R R CN CN base 82 80 81 , R = Me (endo) O , R = H , R = Me 83 O + , R = Me (exo) OAc 58 57, R = H , R = H Ph 67 68 O O , R = Me , R = Me 84 O 78 79, R = Ph , R = Ph O O O R R R Ph Ph Ph 85, R = H 87, R = Ph 88, R = Ph 86, R = Ph

Entry Dipolarophile R Products Ratio H 80 d 1 CN Me 81/82/83 1:1:1 H 85 d 2 Ph Ph 86/87/88 1:6:3 of substituted fulvenes 114 in the presence of base furnished of the type 115, which provide a route to more complex adducts of the type 115b, presumably via initial formation structures.24d of the intermediate 115a followed by a sigmatropic shift.24a,b Sammes and co-workers have described an alternative route In general, all the cycloadditions gave good-to-excellent to the generation of the parent 2-benzopyrylium-4-oxide.25aec yields (57e83%), depending on the nature of the substrates. Cyclohexadiene 117 upon dehydrogenation with palladium on These workers also examined the scope of this cycloaddition charcoal followed by hydrolysis and acetylation gave the re- towards the synthesis of 7-5-8-fused oxa-bridged tricyclic sys- quired acetoxypyranone 118 (Scheme 13). Treatment of the tems of type 11624c (Scheme 12). The same authors have re- acetate 118 with either base or heat generated the reactive in- ported further studies on the transformation of the adducts termediate, 4-oxido-2-benzopyrylium 119, which can be

Table 3 Cycloadducts obtained by the reaction of oxidopyrylium species with various dipolarophiles O O O R O O O R O R O R COOR' OBn COOR' R'OOC R'OOC 89, R = H R' 90, R = H, R' = Me 99, R = H, R' = Me 108 91, R = H, R' = iPr 100, R = H, R' = iPr , R = H, 92, R = H, R' = tBu 101, R = H, R' = tBu R' = OMe 93 102, R = CH OTBS, R' = Me 109, R = H, , R = CH2OTBS, R' = Me 2 94 i 103, R = CH OTBS, R' = iPr R' = CH(OBn) , R = CH2OTBS, R' = Pr 2 95 t 104, R = CH OTBS, R' = tBu (CH2)3OTBS , R = CH2OTBS, R' = Bu 2 96 105, R = (CH ) OTBS, R' = Me , R = (CH2)3OTBS, R' = Me 2 3 97 i 106, R = (CH ) OTBS, R' = iPr , R = (CH2)3OTBS, R' = Pr 2 3 98 t 107, R = (CH ) OTBS, R' = tBu , R = (CH2)3OTBS, R' = Bu 2 3

Entry Dipolarophile R Products Ratio Ref. d 1 OBn H 89 20a MeO2C H 90/99 2:1 2 CH2OTBS 93/102 13:1 21 CO Me 2 (CH2)3OTBS 96/105 4:1 i 91 100 CO2 Pr H / 2:1 3 CH2OTBS 94/103 15:1 21 i CO2 Pr (CH2)3OTBS 97/106 7:1 t CO2 Bu H 92/101 2:3 4 CH2OTBS 95/104 21 t CO2 Bu (CH2)3OTBS 98/107 5CH2]C]CHOMe H 108 d 22 6CH2]C]CH(OBn)(CH2)3OTBS H 109 d 22 3410

O O O- O O Et N O Ph O O 3 H Et N 118 3 O Ph O + CH Cl H Ph + O 2 2 O O+ 95% + rt O Me Me 121a 121b OAc 119 38:3 57 110 Me Me 111 (91%) OEt

74% iPr2NEt CH Cl S S O 2 2 O O O 18 h O O 112 44% O O O O O O + O O O OEt O O OEt + Ph O Ph 122b + S + S S 123b 1:9 123a 122a 49:40 S S O S O O O 113c 113a 113b Scheme 14.

Scheme 11. Even cyclopentene reacted with the ylide 119 to give the endo adduct 124 in 70% yield, along with a small amount of O R the exo isomer 125 (8%) (Fig. 2). The preference for the tran- R 2 R2 1 R1 R R R2 1 Et N 1,5-shift sition state leading to the endo adduct is noteworthy, since 3 O O + O there are no secondary orbital interactions to consider. Cyclo- CHCl3 hexene also reacted to give the endo adduct 126, albeit in low AcO 114 R O R O yield (10%). Interestingly, cyclohexenone, an electron-deﬁ- 57, R = H 115a 115b 67, R = Me cient dipolarophile that generally does not react with pyry- R1 R1 = R2 = Me O R R = R = Ph R2 1 2 lium-3-olates, added in high yield to the benzo analogue 119 R1,R2 = -(CH2)4-, -(CH2)5- etc O to give three adducts, the exo adduct 127, and the isomeric O exo and endo adducts, 128 and 129, in the ratio 21:27:51 O 116 R (Scheme 15). Table 4 summarizes some additional examples of the cycloadditions of oxidopyrylium ylide 119 leading to Scheme 12. adducts 130e136.25c

3.2. Intramolecular cycloadditions O O 1. Pd/C Having established the scope of the intermolecular cycload- O O 2. H3O+ ditions, Sammes and co-workers explored the intramolecular 3. Ac2O/Py OMe 118 OAc 117 cycloadditions of 3-oxidopyrylium. Thus, the acetate 137, Et3N readily prepared from furfural, either on heating or by

O O- O O H H O CO2Me DMAD O O O+ ( ) CO2Me ( )n n H 120 (88%) 119 H 124, n = 1 8:1 125, n = 1 Scheme 13. 126, n = 2

Figure 2. Cycloadducts of 119 with cyclopentene and cyclohexene. trapped with a wide range of dipolarophiles (e.g., DMAD) to yield the substituted benzotropone derivative 120.25a O O-

Benzopyrylium 119 on reaction with styrene, a conjugated Et3N dipolarophile, yielded a mixture of all four adducts 121a,b and O O+ 25c 122a,b (Scheme 14). The lack of regiocontrol in this case is 118 OAc 119 in accord with simple Hu¨ckel molecular orbital calculations, 77% which indicate that the HOMOeLUMO and LUMOe O HOMO interactions between the dipole and dipolarophile O are approximately equal and predict the opposite regiochemis- O O H H try. The reaction of 119 with ethyl vinyl ether gave the endo H O O O + adduct 123a in a major amount, along with the minor adduct O + H H 123b. Here, again, the reverse regioisomer is formed as the 127 H 128 129 O major product (in comparison to that observed in the 3-oxido- O pyrylium series). Scheme 15. 3411

Table 4 O O Adducts obtained by cycloadditions of 119 with various dipolarophiles Δ O O O O O R 78 4 O AcO 137 H H 138 O R O Ph 3 R2 O O H R1 Ph Me Et3N O 131 130 132 60% , R1 = R3 = R4 = H, R2 = CHO O 133 139 , R1 = R2 = R4 = H, R3 = OAc AcO Me 134 142 , R1 = R2 = R3 = H, R4 = OAc O 135 O , R1 = OAc, R2 = R3 = R4 = H Δ 136 , R1 = R3 = R4 = H, R2 = OAc AcOH O O 52% Entry Dipolarophile Products (yield, %) Ratio OH 140 H 143 1 Ph Ph 130 d O O Δ d O 2 131 (75) 60% O d AcO H 3 CHO 132 (45) 141 144

4 OAc 133/134/135/136 (99) 51:3:36:9 Scheme 16. treatment with a base, generated the 3-oxidopyrylium, which asymmetric version of the cycloaddition reaction, despite nu- underwent intramolecular cycloaddition to give the cycload- merous applications of this class of reactions in organic syn- duct 138 in 78% yield (Scheme 16).25b This methodology ap- thesis. Recently, Mascarenas and co-workers have reported peared to be general and, depending on the length of tether, an interesting method for the synthesis of chiral oxabicyclic various ring systems could be accessed in a stereocontrolled adducts.28 The authors envisaged that the introduction of a ho- fashion. The acetates 139e141 gave the cycloadducts mochiral p-tolylsulfinyl group at the trans-terminal position of 142e144, respectively, after generation of the corresponding the alkene moiety may induce a diastereodifferentiation in the ylides followed by intramolecular cycloaddition.2,25b Simi- intramolecular cycloaddition. Thus, the 2-substituted furan larly, the substrates 145 and 147 were also reported to give 152 was prepared from 151. The reaction of the compound the cycloadducts 14626 and 14827 upon appropriate treatment 152 with the enantiopure iodosulfinyl derivative 153 furnished (Eqs. 1 and 2). optically active 2-furylcarbinol 154. Compound 154 was then subsequently transformed into pyrylium ylide precursor 155, O O which, upon treatment with DBU in toluene, provided the cy- OMe 1. AcCl, Py OMe OMe CH2Cl2 O OMe cloadducts 156 and 157 having 156 as the major product. The O 2. DBU ð1Þ ratio of adducts depends on the solvent and the experimental HO 86% Me conditions. Desulfinylation of the cycloadduct 156 with Raney 146 145 Ni in refluxing THF afforded the oxa-bridged carbocycle (þ)- 158 (Scheme 17).

OH MeO MeO OTBS 140 °C OH COOEt ii OTBS COOEt O OAc sealed tube MeO H ð2Þ OHC i O O MeO COOEt COOEt MeOO O COOEt .. OMe 152 COOEt O 151 - O S 147 148 154 pTol iii, iv

O Interestingly, the acetate 149 endowed with a tether having O O COOEt an allenic moiety also underwent a smooth cycloaddition upon COOEt v O COOEt COOEt treatment with DBU to give the adduct 150 in excellent yield O COOEt + .. HO .. O 22 ..H H COOEt (Eq. 3). S H - - S H 156 -O S O O O pTol 157 O 155 DBU pTol pTol AcO vi O CH Cl .. 2 2 BnO O ð3Þ O - OBn 81% TBSO OTBS COOEt O S CH2=C=CH pTol 149 150 O COOEt 153 I H 158 3.3. Asymmetric cycloadditions Scheme 17. Reagents/conditions: (i) nBuLi, furan, THF, 78 C, after 10 min Et3N, TMSCl, 83%; (ii) NaH, THF, 153,0 C, 93%; (iii) TBAF, AcOH, THF; One of the most important aspects that have received rela- (iv) NBS, THFeH2O, 92% (both steps); (v) acetylation and DBU, toluene, tively little attention in [5þ2] annulation methods is the 30 C, 86%; (vi) Raney Ni, THF, 82%. 3412

Recently, Trivedi and co-workers demonstrated that the re- 4. Oxidopyrylium species from b-hydroxy-g-pyrones actions of optically active aldehydes derived from sugar deriv- and their cycloadditions atives with 2-lithiofuran provide 2-furylcarbinol intermediates, which led to a convenient and flexible route to optically pure b-Hydroxy-g-pyrones have also been proved to be a versa- oxabicyclo[m.n.0]adducts via intramolecular cycloaddition of tile source of oxidopyrylium species and their intra- and inter- oxidopyrylium species.29,30 Thus, the chiral furylcarbinol molecular cycloadditions have led to the development of novel 161 was synthesized from the chiral aldehyde 160, which general routes to structurally diverse oxa-bridged molecular was prepared from ribose 159. The furylcarbinol 161 was frameworks, which are not readily accessible otherwise. then converted into the 3-oxidopyrylium zwitterion 162, which Many elegant synthetic applications of the cycloaddition of underwent cycloaddition with the tethered olefin to afford the oxidopyrylium species derived from b-hydroxy-g-pyrones cycloadducts 163 and 164 as an inseparable mixture of have been reported and some developments have been delin- diastereomers (93:7) in 65% yield (Scheme 18). Following eated below. a similar synthetic strategy and exploitation of the pseudo- symmetry of ribose, the same authors synthesized the [5þ2] ad- 4.1. Intramolecular cycloadditions duct 167 via the carbinol 165 and the acetate 166 (Scheme 19). Efforts to use the hydroxypyranone 168 in the cycloadditions of Garst and co-workers reported that the thermolysis of py- 3-oxidopyrylium, were, however, reported to be unsuccessful.30 rones derived from kojic acid, such as 171, promotes an inter- Based on earlier studies by Bartlett and co-workers,31 Trivedi nal [5 2] cycloaddition.32 This observation provided the first and co-workers reasoned that this failure could be a consequence þ evidence that b-hydroxy-g-pyrones could serve as an alterna- of the existence of the hydroxypyranone 168 predominantly tive source of the five-carbon component in the cycloaddition. in the form of the hemiketals 169 and/or spiroketals 170 Thus, pyrolysis of amides 171 and 173 in refluxing benzene (Scheme 20). provided the cycloadducts 172 and 174, respectively, in moderate yields (Scheme 21). Similarly, the substrates 175 and 177 having three- and four-atom tethers also underwent cycloaddi- Me Me Me tion to give the corresponding adducts 176 and 178, respec- Me O O O O OH i tively (Scheme 22).32 HO O OH O HO CHO OH OH BnO 159 160 161 HO H D-ribose ii-iv 80 °C O O O O NMe Me Me Me Me Me Me Ac2O/Py O O - NMe AcO O O O O O O O O O 171 172 (70%) + HO O O + OBn OBn O BnO 80 °C O H H O O O NMe 3:97 164 163 162 Ac2O/Py NMe AcO O n Scheme 18. Reagents/conditions: (i) BuLi, furan, THF, 78 C, 70%; (ii) O 173 174 (42%) t VO(acac)2, BuOOH, CH2Cl2; (iii) Ac2O, Py, DMAP, CH2Cl2, 88% (two steps); (iv) Et3N, MeCN, reflux, 65%. Scheme 21.

Me Me Me Me Me Me HO O O O O O O O O O 80 °C i, ii iii O O AcO O H Ac2O/Py O O OH AcO O AcO OAc CO2Me CO2Me H 167 CO Me MeO C 165 166 2 2 OAc 175 176 (70%) t Scheme 19. Reagents/conditions: (i) VO(acac)2, BuOOH, CH2Cl2; (ii) Ac2O, HO O Py, DMAP, CH2Cl2, 88% (two steps); (iii) Et3N, MeCN, reﬂux, 83%. O O 80 °C AcO O H ( ) 2 Ac2O/Py

CO2Me MeO2C MeO2C CO2Me Me Me Me Me 177 178 (65%) O OH O O O O O HO Scheme 22.

HO O O OH OH O O Me O The aforementioned cycloadditions apparently proceed 169 168 Me O HO 170 through migration of the group (R) from O3 in IV to O4 of Scheme 20. the carbonyl group, resulting in the formation of an 3413 oxidopyrylium species such as V that undergoes subsequent (TfOH) and trimethyl orthoformate (dehydrating agent) pro- cycloaddition to give the adducts of type VI, as shown in vided the adducts 187 and 189, respectively (Scheme 26). In Scheme 23.5b,33,34 It appears that this type of group transfer fact, Garst and co-workers reported that substrate 190, which is rate limiting and it is an important criterion for the reaction decomposed under thermolysis, did provide the cycloadduct to occur and frequently requires high temperatures. For in- 191 when treated with methanesulfonic acid in reﬂuxing stance, the compound 179 on pyrolysis in toluene at 200 C MeOH (Scheme 27).32 gave the cycloadduct 180, whereas 181 decomposed under these conditions (Scheme 24).35 HO O TfOH MeO O - O O group O O MeOH, Δ MeO O R transfer 75% O S S O activation R RO O 186 187 O+ O HO O V VI IV TfOH MeO O O O MeOH, Δ MeO Scheme 23. 78% O O 188 189

Scheme 26. O O OTBS OTBS O 200 °C O MeO C CO Me CO2Me O 74% TBSO O H OTBS 2 2 CO2Me OTBS MeSO3H OTBS MeOH 179 180 181 OO reflux, 12 h O OMe 85% Scheme 24. OH 190 191 OMe O

In order to avoid the requirement of high temperatures, Scheme 27. Wender and co-workers developed an alternative and milder activation process to perform the cycloaddition, even at room temperature. This involves an initial O-4 alkylation, to produce a highly reactive 4-alkoxypyrylium salt, followed 4.2. Intermolecular cycloadditions by O-3 desilylation to give the desired oxidopyrylium intermediate. Thus, alkylation of 182 with methyl triflate (MeOTf) at There are only a limited number of examples on the inter- 20 C for 8 h generated the pyrylium salt 184 (Scheme 25). molecular cycloadditions of b-hydroxy-g-pyrones. Although Upon exposure of the salt 184 to anhydrous ceasium fluoride, the reaction between b-hydroxy-g-pyrones and alkenes cycloaddition proceeded smoothly at room temperature to give has been shown to proceed efficiently in the intramolecular cy- the cycloadduct 185 as a major product. Interestingly, this pro- cloaddition mode, cycloaddition in the analogous intermolec- tocol permitted the direct use of hydroxypyranones such as ular variant either fails completely or provides a mixture of 183. Under these conditions, the intramolecular cycloaddition stereoisomers. Wender and Mascarenas have reported a few proceeded in one pot directly from the hydroxypyranone 183 examples of the cycloaddition of highly reactive 4-methoxy- at room temperature to give the cycloadduct 185 as the major 6-methyl-3-oxidopyrylium ylide 193 with various olefinic di- product in good yields.35 polarophiles.33 The 3-oxidopyrylium 193 was prepared from Mascarenas and co-workers have reported the acid-pro- a-deoxykojic acid 192, and intercepted with olefins to give ad- moted [5þ2] cycloadditions of pyrones.36 These authors re- ducts of the type 194, as shown in Scheme 28. The pyrone 192 ported that pyrones such as 186 and 188 on refluxing in was converted into the highly reactive 4-methoxy-3-oxidopyry- methanol in the presence of trifluoromethanesulfonic acid lium ylide 193 by treatment with N,N-dimethylaniline. This

O OR MeOTf OR CsF CH2Cl2/DMF CH2Cl2 MeO O H O O MeO O+ or TMP OBz OBz OBz CH2Cl2, rt 185 182, R = TBS 184 TfO- 82-84% 183, R = H

Scheme 25. 3414 transient species was then trapped with various dipolarophiles the cycloaddition as well as permit further manipulation of to provide the corresponding cycloadducts 195e200 (Table 5). the adducts of the type VIII leading to functionalized and substituted oxabicyclo[3.2.1]octanes of the type IX, which

Me are not accessible through intermolecular cycloaddition MeO Me z + (Scheme 30). O MeOTf Me O O O O MeO PhNMe2 O CH2Cl2 O O HO Δ, 4 h OH OR RO RO 192 z O O 193 194 O R1 Scheme 28. R X X 2 VII VIII IX

Table 5 Scheme 30. Cycloadducts derived from 193 and various dipolarophiles Me O Thus, thermolysis of the thioether 203, which can be pre- Me Me H CO2Me NPh pared by standard procedures, in toluene at 145 C for 40 h R2 O 38 O MeO O MeO provided a single exo adduct 204 in 71% yield. Treatment MeO CO2Me R1 H O O of the cycloadduct 204 with Raney Ni effected desulfurization O O 197 198 and rearrangement to the ketone 205 in 70% yield (Scheme 195a Me O Me , R1 = CN, R2 = H 31). Interestingly, other substrates such as 206 having a sulfone 195b H H , R1 = H, R2 = CN 196a moiety in the tether underwent smooth cycloaddition to give , R1 = Ph, R2 = H NPh 196b O O 39 , R1 = H, R2 = Ph MeO MeO 207 in excellent yield at a considerably lower temperature. H O H O O Similarly, the substrate 208 readily underwent cycloaddition 199 200 and the resulting adduct was transformed into the diol 209 that is not readily accessible otherwise (Scheme 31).38 Entry Dipolarophile Products (yield, %) Ratio CN 1 195a/195b (65) 2.3:1 O TBSO OTBS Ph TBSO 2 196a/196b (58) 1:2.2 O H Raney Ni O O O O H 71% 70% Me 3 DMAD 197 (60) S S 203 204 Me O 205 O O 4 NPh 198/199 (73) 1.8:1 OTBS TBSO 90 °C O H O O 18 h 91% S O O S 5 200 (73) 1:0 206 207 O O

BzO O TBSO BzO mCPBA Guitian and co-workers demonstrated that the generation of O O O O O H SiMe2 KF benzyne in the presence of a-deoxykojic acid 192 also leads to O H OH SiMe2 209 cycloaddition and gave the benzo-fused adduct 202 in moder- 208 O OH ate yield (Scheme 29).37 Scheme 31.

Me O Me DME 4.3. Asymmetric cycloadditions + Δ PhO O HO 33% O 201 O 202 Ohkata and co-workers reported an asymmetric version of 192 the pyranoneealkene cycloaddition by placing chiral auxilia- Scheme 29. ries in the tether. By using ()-menthyl and ()-8-phenylmenthyl as the chiral auxiliaries, moderate levels of The low success rate of intermolecular reactions of the diastereoselectivity were observed.40 Thus, the substrates b-hydroxy-g-pyrones prompted Mascarenas and co-workers 210aee on reaction with TBSOTf in the presence of 2,6-lut- to develop an alternate route to the synthesis of oxabicy- idine underwent cycloaddition at room temperature to give clo[3.2.1]octane ring systems by employing temporary tether- the cycloadducts 211aee, respectively (Scheme 32). ing strategies. The authors envisaged that tethered Mascarenas and co-workers have reported an ingenious hydroxypyrones, especially with alkenyl chains containing approach for the synthesis of enantiomeric partners of a heteroatom, such as VII, would increase the efﬁciency of oxabicyclic adducts, by intramolecular cycloadditions of 3415

O MeO C MeO2C R O 2 1 CO Me R CO2Me TBSO 2 2 O TBSOTf R1O O R Raney Ni O O 2 H H O 2,6-leutidine O 71-83% O RBSO H CO2R3 S R O C CO2R3 R3O2C O (-)-218 3 2 213 .. 211a-e pTol 210a-e a , R1 = Bz, R2 = H, R3 = (-)-menthyl MeO2C b, R = Bz, R = Me, R = (-)-menthyl CO Me 1 2 3 O 2 CO2Me c, R = Bz, R = Me, R = (-)-8-phenylmenthyl TBSO 1 2 3 RBSO d CO2Me Raney Ni , R1 = TBS, R2 = Me, R3 = (-)-menthyl O H O O e, R1 = TBS, R2 = Me, R3 = (-)-8-phenylmenthyl H 66% - S+ H Scheme 32. TsN + O 217 (+)-218 pTol -

Scheme 34. b-hydroxy-g-pyrones having tethers that contain a chiral alkene moiety. Cycloaddition of the pyrone with the tethered olefin having a homochiral p-tolylsulfinyl group at the trans- 5. Cycloaddition of oxidopyrylium species (from terminal position led to an excellent level of diastereodifferen- acetoxypyranones and/or b-hydroxy-g-pyranones) tiation.39,41 Thus, the pyrone 212 underwent cycloaddition in the synthesis of natural products upon heating to give the adducts 213 and 214 with excellent diastereoselectivity, having 213 as the major product (Scheme Cycloaddition reactions of 3-oxidopyrylium species, which 33).41 Other pyrone derivatives also led to high diastereoselec- can be generated from either the acetoxypyranones or the tivity and gave the corresponding adducts in excellent yields.41 b-hydroxy-g-pyranones, with alkenes provide a general, versatile, and stereocontrolled entry into highly functionalized oxa- bridged cycloadducts, which have enormous potential for the MeO C 2 MeO2C EtO2C CO2Me synthesis via manipulations of the oxygen bridge and other CO2Et CO2Me TBSO O O functionalities. It is evident that such manipulations in the cy- toluene H H O + O TBSO H cloadducts obtained from intermolecular cycloaddition have O O 110 °C TBSO H S S 99% O O potential for the synthesis of functionalized seven-membered .. .. S pTol pTol carbocycles, whereas the adducts derived from an intramolecu- 212 .. O 213 214 p-Tol (97:3) lar reaction may lead to more complex molecular architectures. Therefore, it is not surprising that the cycloaddition (inter- as EtO C MeO2C 2 CO Et EtO C CO Et 2 CO2Me well as intramolecular) of oxidopyrylium species has been em- 2 2 TBSO O toluene H ployed as a key strategic element in designing the synthesis of O - O O 110 °C RBSO ++ O H various types of heterocyclic and carbocyclic natural products. - S 88% S++ TsN + + - O - Some typical applications are described below. p-Tol - S O- TsN TsN pTol p-Tol Sammes and co-workers have successfully completed the 215 216 217 + synthesis of a sesquiterpene, b-bulnesene 221, employing an other diastereomer (10%) intramolecular [5þ2] acetoxypyranoneealkene cycloaddition 46,47 Scheme 33. strategy. The acetoxypyranone 219 was heated in acetonitrile at 150 C for 20 h, and the resulting 3-oxidopyrylium un- Later, Mascarenas and his associates discovered that trans- derwent intramolecular dipolar cycloaddition to produce the forming the sulfoxide into an appropriate sulfoximine would desired isomer 220a and the unwanted 8-methyl epimer 220b in a ratio of 1:5 (Scheme 35). The mixture was elabo- reverse the diastereofacial selectivity of the cycloaddition. 46 The transformation of sulfoxide into sulfoximine can be read- rated into bulnesene 221 and its epimer. ily performed with an aminating agent such as O-mesitylsul- O fonyl-hydroxylamine (MSH) and takes place with retention R 42e44 O 1 Me of configuration. Thus, the pyrone 216, derived from Me MeCN R H 215, underwent intramolecular cycloaddition to give the ad- O O H 2 42 Me 150 °C duct 217 in good diastereomeric excess (Scheme 33). The 20 h, 75% OAc Me 220a, R1 = Me, R2 = H adducts 213 and 217 were desulfinylated to afford the enantio- Me 219 220b, R1 = H, R2 = Me 221 pure oxabicyclic compounds ( )-218 and ( )-218, respec- + þ a:b = 1:5 tively (Scheme 34). Thus, both the enantiomeric oxabicyclic 4-epi-β-bulnesene adducts can be readily synthesized by an appropriate choice Scheme 35. of chiral auxiliary. Recently, Mascarenas and co-workers reported the theoretical rationalization for the difference in the The formation of the incorrect methyl epimer 220b as the nature of the diastereofacial selectivities, which supported major cycloadduct was probably due to steric repulsions their experimental observations.45 between the methyl group and the aromatic ring in the 3416

3-oxidopyrylium intermediate. This problem was overcome by Wender and co-workers have developed elegant applica- employing the pyranulose acetate 222 as a precursor. Thus, tions of the [5þ2] cycloaddition of oxidopyrylium species in pyranulose acetate 222 upon heating in acetonitrile at the synthesis of various types of natural products.50e54 Earlier, 150 C or on treatment with 1,5-diazabicyclo[4.3.0]non-5- they reported the ﬁrst synthesis of racemic phorbol51 and they ene (DBN) at room temperature furnished the cycloadduct have recently reported a formal asymmetric synthesis of phor- 223 in 61% yield. Hydrogenation over PdeC/EtOH produced bol.52 The chiral acetoxypyranone 235 was treated with DBU the required epimer, which, on further chemical manipula- to give the cycloadduct 236 in a highly stereoselective fashion tions, readily provided ()-4b-bulnesene (Scheme 36).47 (Scheme 39).52 The adduct was elaborated into the compound 237, which was converted into 238 having a phenylacetylene group, which, upon cyclization with Cp2ZrCl2, gave the alco- O Me hol 239. Oxidation of 239 furnished the intermediate 240 in an O Me H O DBN optically pure form (Scheme 39). In order to demonstrate the O H CH2Cl2 Me utility of 240 as a precursor to phorbol, the authors also devel- OAc rt, 61% 223 221 Me oped a route to phorbol 241 from the racemic intermediate 222 β (+ - )-4 -bulnesene 240. The same workers have developed a synthesis of (þ)-resiniferatoxin via the chiral pyranulose acetate 242, which, on Scheme 36. reaction with base, gave the optically pure adduct 243 (Scheme 40). The adduct 243 was elaborated into (þ)-resini- Sammes and co-workers reported a Lewis acid-catalyzed feratoxin (an ultrapotent analogue of capsaicin and the most rearrangement in compounds of the type 224 to the cis-fused potent irritant known), after a series of transformations.53 bicyclo[4.4.0]decane 226 via the species 225 (Scheme 37).46 Treatment of the keto-alcohol 226 with triethylamine readily O OAc O Me gave the trans-isomer 227. This rearrangement was exploited OAc Me OAc i in the synthesis of valerane-type sesquiterpenes. The acetoxy- O H O O pyranone 228 was transformed into the cycloadduct 229 by OAc Me O OTBS H treatment with Et N in acetonitrile. Conjugate addition of 235 H 3 236 OTBS 237 the isopropyl group followed by Grignard reaction with meth- OTBS ylmagnesium bromide produced the alcohol 230 (Scheme 38). OH ii Me The alcohol 230 on treatment with TiCl4 afforded ()-crypto- H Me OAc fauronol 231. Treatment of 231 with Ac2OeNaOAc gave ()- Me iii Ph O H fauronyl acetate 232, which was elaborated into valeranone O 48 OTMS 233 and valerane 234 (Scheme 38). Sammes and his associ- OTMS H Ph OTBS ates have also employed cycloadducts of oxidopyrylium spe- 239 238 OTBS 49 iv cies for the synthesis of other terpenoids. O OHMe Me Me Me OH H O O H H OH + H H Me Me O Me Et N Me SnCl4 3 O H O Me HO H O Me OH OH HO H OTMS OTBS H H Ph 241 OH phorbol 224 227 240 225 226 (60%) Scheme 39. Reagents/conditions: (i) DBU, MeCN, 79%; (ii) PhCCLi, LiBr, Scheme 37. n THF, HMPA, TMSCl, 75%; (iii) Cp2ZrCl2, BuLi, THF, AcOH, 93%; (iv) PCC, NaOAc, CH2CL2, 94%.

Me OH Wender and his associates have recently reported a number O O ii, iii i O of intramolecular cycloadditions with a view to develop a gen- O Me O Me Me Me eral route to the BC-ring system of C12-hydroxy daphnetox- 230 ins.54 Thus, the intermediates 244a,b on treatment with OAc 228 229 Me DBU in acetonitrile at 80 C gave two adducts 245a,b and iv 246a,b in which the isomer 245 was favoured (Scheme 41). Me X Me O Me OH Me Y Me Me Interestingly, the protecting group in the tether was found to 54 Me Me v Me control the stereochemistry of the cycloaddition. O AcO Magnus and co-workers have employed an intramolecular Me Me Me [5þ2] cycloaddition of an oxidopyrylium species towards 233, X,Y = =O, 232 231 234, X = Y = H their studies on the synthesis of the BC-ring system of tax- 55,56 i anes. Thus, the acetoxypyranone 247 on treatment with Scheme 38. Reagents/conditions: (i) Et3N, MeCN, 80 C, 94%; (ii) PrMgBr, CuBr, Me2S, ether, 86%; (iii) MeMgI, ether, 85%; (iv) TiCl4,CH2Cl2, 83%; DBU in reﬂuxing toluene gave the cycloadduct 248 as the ma- (v) Ac2O, NaOAc, 82%. jor product, which was converted into the cyanoenone 249. 3417

Me Ph O Me Me Me OAc H O O OAc O Me OBn DBU O H O OBn O H O H MeCN O OH OAc 84% OTBS O OTBS 242 243 (+)-resiniferatoxin OMe

Scheme 40.

Me OR Me Me O Me OR O Me OR OBn O i-iii DBU OBn H OBn + H O O Li O OAc H MeCN O + OBn O Me O OR OBn Me Me Me OBn 80 °C OTBS OH 246a,b Me 253 Me 244a, R = TBS 245a,b 252 OR 254 244b, R = Ac OR R = OTBS (3.5:1) (84%) iv Me R = Ac (5:1) (79%) Me Me Scheme 41. Me v OH O Me Me O Cyclopropanation in 249 gave the compound 250, which upon Me Me 255 O cleavage of the cyclopropane ring furnished the compound 256 O 55 251 having the BC-framework of taxanes (Scheme 42). Scheme 43. Reagents/conditions: (i) CeCl3, THF, 90%; (ii) SOCl2,Py, n CH2Cl2, 94%; (iii) CsF, Bu4NCl, MeCN, 97%; (iv) O2, hn,CH2Cl2, OAc MeOTBS MeOTBS MeOH, Rose Bengal, Me2S; (v) CF3COOH, CH2Cl2, 62% (both steps). i O O ii, iii NC O O O 1. Ac O, O Me Me 2 Me O Et3N OTBS O OTBS O OTBS 248 249 2. PhH Me OTBS O Me Δ 247 iv Me HO Me 257 258 (80%) MeOTBS MeOTBS NC NC v Scheme 44. Me O Me O Me Me O 251 250 O rearrangement in 262 followed by acetylation furnished the OTBS OTBS macrocyclic pyranulose acetate 263 that, upon treatment Scheme 42. Reagents/conditions: DBU, toluene, 110 C, 1.5 h, 77%; (ii) Br2, with DBU, gave the natural product 264. Et3N, 100%; (iii) NaCN, PTC, 96%; (iv) Me2C]PPh3, THF, 78 C to rt, 95%; (v) sodium naphthalenide, THF, 78 C, 100%. OH I O i OH Magnus and Shen have also used this dipolar cycloaddition Me O Me 259 O 260 strategy for the synthesis of the cyathin diterpene skeleton Me 57 Me (Scheme 43). Thus, addition of furyllithium 253 to the ke- OH tone 252 followed by further manipulation of the adduct CHO OH ii, iii O gave the precursor 254. Oxidation of 254 with singlet oxygen O Me iv,v gave the precursor 255 required for the generation of the oxi- Me Me O Me O O 262 dopyrylium species. Treatment of pyranulose 255 with tri- 261 O Me ﬂuoroacetic acid gave the cycloadduct 256 containing the Me 57 O tricyclic network of cyathin (Scheme 43). Similarly, the O AcO compound 258 was prepared from the precursor 257 with vi O Me O Me H a view to synthesize the perhydroazulene portion of the diter- Me 58 Me O O pene antibiotic, guanacastepene (Scheme 44). H 264 59 Recently, Pattenden and co-workers reported an elegant (+)-intricarene O 263 biomimetic synthesis of a highly complex natural product, O (þ)-intricarene. The synthesis involves a transannular dipolar Scheme 45. Reagents/conditions: (i) 3-methyl-6-trimethylstannylfurfural, cycloaddition of an oxidopyrylium species (Scheme 45). Pd(PPh)4, CuI, CsF, DMF; (ii) NBS, Ph3P, 72% for both steps; (iii) CrCl2, t Thus, the optically pure macrocycle 262 was synthesized 4A˚ MS, THF, 70%; (iv) VO(acac)2, BuOOH, CH2Cl2, 20 C; (v) Ac2O, from the epoxyalcohol 259, via 260 and 261. Oxidative Et3N, DMAP, CH2Cl2, 30%, two steps; (vi) DBU, MeCN, reﬂux, 1 h, 10%. 3418

In contrast to the intramolecular versions, there have been O O relatively few examples of the utilization of intermolecular cy- Me O O Me + Me Me cloadditions for the synthesis of natural products. This could 271aCN NC be partially attributed to the subtle reactivity of oxidopyrylium 271b CN zwitterions in the intermolecular versions and a low degree of MeCN Δ, 45% MsCl, stereocontrol in these cycloadditions, compared to their intra- i- CN Pr2EtN molecular counterparts. O MsCl, OAc O Me i- Ohmori reported the synthesis of a bicyclo[4.3.1]decane Pr2EtN O CHO Me Me ring system in his studies towards the synthesis of phomoi- Me O O MeCN Δ NC OAc 269 , 48% dride B (CP-263114) via an intermolecular [5þ2] oxidopyry- Me OH 272 liumealkene cycloaddition as a key step (Scheme 46).60 Thus, 270 CN O 265 the reaction of the acetate and dimethyl fumarate in the Cl O Me presence of triethylamine gave the adducts 266a,b having i- Me MsCl, Pr EtN 2 NC Cl 266a as the major product and 266b as the minor product. MeCN, Δ, 30% 273 The adduct 266a was manipulated to give the functionalized cycloheptanone derivative 267, which, upon intramolecular al- O MsO dol condensation followed by oxidation, furnished the bridged O O NaH, THF O Me Me Me Me O bicyclic compounds 268a,b containing the bicyclo[4.3.1]- Me Δ Me NC HO Bu 77% decane ring system of phomoidride B. 271b 274 275

Scheme 47. O OTBS O O CO2Me O + O Et3N OTBS OTBS + MeCN, O MeO C CO Me MeO2C Δ, 77% MeO2C CO2Me 2 2 O HO OAc 28 266a 266b H H (13:1) O 265 indene O O O O Et N, CH Cl 3 2 2 H H H H O CHO rt, 60% 277 1. DBU OAc 276 + 57 TBSO O O 2. PCC TBSO H TBSO H H MeO2C CO2Me MeO C CO Me MeO C CO Me O 2 2 2 2 267 268a 268b (4:1) (82%) OH 278 H Scheme 46. Scheme 48. Heathcock and co-workers reported the synthesis of 2,7-di- oxatricyclo[4.2.1.03,8]nonane in the context of model studies stereocontrol to provide the single isomer 276, in good yield, directed towards the synthesis of dictyoxetane.61 The hydroxy- which was elaborated into 277 and 278 (Scheme 48).62 pyranone 270 was prepared from 5-methylfurfural 269. Mesy- Baldwin and co-workers63 have examined the cycloaddition lation of 270 and thermolysis in the presence of acrylonitrile of oxidopyrylium species in detail and have recently gave a mixture of adducts containing 271a,b, whereas the re- reported63a,b an excellent biomimetic approach to tropolone action of the dipolar species derived from 270 with a-acetoxy- natural products and a synthesis of deoxy epolone B that em- acrylonitrile and chloroacrylonitrile gave single adducts 272 ploys cycloaddition of tropolone ortho-quinone methide, and 273, respectively (Scheme 47). A detailed study of some which was prepared via dipolar cycloaddition of oxidopyry- of these adducts was carried out in order to develop a route to- lium species. The pyranulose acetate 279, readily available wards the synthesis of dictyoxetane. After studying various from 3-methyl-methylfuroate, was heated with acetoxyacrylo- types of transformations, compound 271b was elaborated nitrile to give the adduct 280. This was converted into tropo- into the hydroxymesylate 274, which, upon treatment with so- lone 281 in a few steps, which upon thermal activation in dium hydride, furnished the compound 275 having the tricy- the presence of humulene provided deoxy epolone B 283 via clic network of dictyoxetane. the intermediate 282 (Scheme 49).63a Very recently Trivedi and Murali have reported an expedi- Snider and co-workers64a,b designed an efﬁcient synthesis tious entry into the fused 7-5-6 tricyclic skeleton related to the of cartorimine 289 and descurainin 288 that contain an oxabi- diterpene natural product, FCRR-Toxin. Their strategy is cyclo[3.2.1]octane framework in their molecular structure. based on the premise that the intermolecular cycloaddition The desired pyranulose diacetate 285b was prepared from 5- of 3-oxidopyrylium with indene may result in the formation acetoxymethylfurfural 284 and subjected to cycloaddition of the required skeleton with the correct regio- and stereo- with various styrene derivatives 286 to give the adduct 287, chemistry.62 Indeed, the reaction of 57 with indene in the which was further manipulated to give descurainin 288 presence of base proceeded with exceptional regio- and (Scheme 50). Similarly, cartorimine 289 was synthesized 3419

64a,b O readily, as shown in Scheme 50. Recently, Snider’s group Me O i Me Me O O has also achieved a formal synthesis of polygalolides A and B TBSO PhS O OH employing the cycloaddition of oxidopyrylium species derived OAc OAc CN 281 OTBS 279 280 HO from the diacetate 285b. Thus, the diacetate 285b was treated ii with 290 in the presence of triethylamine, which gave the Me Me adduct 291 in moderate yield, which upon treatment with Me O Me ceasium carbonate followed by acidiﬁcation gave the interme- O Me HO OH diate 292, a known precursor for polygalolides A and B O 64c O H 282 (Scheme 51). Me 283 The cycloaddition of oxidopyrylium species derived from hydroxypyrones has also been employed in the synthesis of Scheme 49. Reagents/conditions: (i) a-acetoxyacrylonitrile, toluene, 120 C, 6 h, 54%; (ii) humulene, p-xylene, sealed tube, 150 C, 24 h, 22%. natural products. In their pioneering work in this area, Wender and his group reported one of the most complex and elegant examples of cycloaddition in their synthesis of phorbol 65a O (Scheme 52). The pyranone 294 was prepared using HOOC O O a Claisen rearrangement in 293 followed by silylation. Heating i-iii vii, viii a solution of the silylated derivative 294 at 200 C for 48 h OHC O OAc RO O leads to the exo cycloadduct 296 as a single diastereoisomer 284 OAc 285a, R = H OH 285b, R = Ac via intramolecular cycloaddition in the oxidopyrylium species iv 295. This compound was efﬁciently elaborated into the poly- OH 289 cartorimine cyclic compound 297, a known precursor of phorbol. Most re- O O cently, the intermediate 185 (prepared earlier by Wender’s O O OMe group; see Scheme 25) was elaborated into ABC-ring systems v, vi 65b OR of 1a-alkyl daphnane analogues. OAc OAc OMe In the context of a synthesis of colchicine, Garst and 286 e OMe OMe MeO OMe McBride examined intramolecular pyrone alkene cycloaddi- OH 288 OR tion in several substrates and transformations on some of the 287 R = TBS 66 descurainin adducts. The precursor 298 underwent cyclization to give

299 under simple thermal activation. The acetoxypyrone 300 Scheme 50. Reagents/conditions: (i) NaBH4, EtOH, 0 C; (ii) Br2, MeOH, gave a mixture of products including the cyclized compound, H2O; (iii) Ac2O, Py, DMAP; (iv) 286,Et3N, CH2Cl2,25 C, 2 d, 31% from 285a; (v) Py$HF, THF, Py; (vi) KOH, MeOH, H2O, 87%, both steps; (vii) whereas the precursors 301a,b, bearing a TMS group at the 4-acetoxymethylcinnamate, MeCN, 175 C, 2,6-di-tert-butylpyridine; (viii) terminal position of the alkene, failed to undergo cycloaddi- KOH, EtOH, H2O, 6, 13% from 285a. tion, probably due to steric reasons (Scheme 53). In addition to the construction of seven-membered rings, the adducts obtained by the cycloaddition of oxidopyrylium O O species also served as useful precursors for the synthesis of tet- 67 O O O ii rahydrofurans. Mascarenas and co-workers have success- 285b O i + O O fully employed the [5þ2] cycloadducts in the synthesis of O O 67a,b 67c 290 O racemic as well as (þ)-nemorensic acid 304, which is OAc 292 291 (34%) the diacid part of the pyrrolizidine alkaloid, nemorensine. Scheme 51. Reagents/conditions: (i) Et3N, CH2Cl2,25 C, 16 h, 34%; (ii) The optically pure compound 303 was synthesized from 302 Cs2CO3,aqTHF,50 C, then acidify, pH 1, 57%. via cycloaddition and reaction of the major adduct with Raney

O O t-BuMe2 1. EtOH OTBS O- Si Me O 78 °C 200 °C O 2. TBSCl O + O imidazole O Me TBSO OH Me OTBS 295 293 294 (62%) O Me Me phorbol H O Me H O H O TBSO O O OTBS OTBS Me 296 Me 297 (71%)

Scheme 52. 3420

OAc O O OMe OMe TBSO TBSO R1 R2 O O AcO O OMe O OMe Δ H R1 H O O OMe OMe toluene H R2 CN 160 °C CN z Z' z 299 CN NC 298 Z' (61%) Z = Z' = COOCH2CCl3 308a 307 , R1 = R2 = Me (82%) 308b OAc , R1 = H, R2 = OTBS (80%) R OAc OMe O OMe O O OMe CN TBSO CN R R R1 CN O O OMe TBSO 1 2 OMe O CN OMe O O R toluene 2 z Z' H H t 160 °C BuO2C t CO2 Bu 301a t 309 310a, R = R = Me (81%) , Z = Z' = CO2 Bu, R = TMS 1 2 301b t 310b, R1 = H, R2 = OTBS (83%) 300 , Z = CO2 Bu, Z' = H, R = TMS

Scheme 53. Scheme 56.

Ni. Treatment of 303 with TBAF and subsequent cleavage and 7. Transformation of dimer of 3-oxidopyrylium oxidation furnished (þ)-nemorensic acid (Scheme 54).67c In this context, it may be mentioned that Trivedi and his co- In the previous sections, we have presented the cycloaddi- workers have also recently reported the transformation of the tions of oxidopyrylium with various alkene dipolarophiles and adducts 70 and 85 into tetrahydrofurans 306a and 306b, the chemistry of the adducts. In the absence of a suitable dipo- respectively, via a Beckmann rearrangement in 305a,b larophile, however, these species undergo dimerization. The 68 (Scheme 55). dimerization reactions of various reactive carbonyl ylides are O 71 TBSO Me HOOC well documented. Hendrickson and Farina reported that OTBS HOOC Me O the 3-oxidopyrylium derived from 57 also undergoes self-di- i, ii iii-v S O O Me Me Me O H merization in the absence of dipolarophiles to give the dimer Me 72 302 311 (Scheme 57). These authors have suggested that the di- Me (+)-304 303 (57%) (69%) mer 311 is a potential precursor for the medium-ring com- : SO pounds. It is rather surprising that, despite its synthetic p-Tol potential, the dimer has not received due attention. Scheme 54. Reagents/conditions: (i) toluene, 6; (ii) Raney Ni, THF, 6; (iii) TBAF; (iv) Pb(OAc) , MeOH; (v) CrO ,HSO , acetone. 4 3 2 4 - O O O O Et3N 60% AcO O O O 57 + O NOH O OMe 311 O iii i, ii O O O O O H2, Pd-C O CN H2, Pd-C 311 R X R EtOH EtOH R 70, 305a, 306a, H , Pd-C, R = OEt R = OEt (95%) R = OEt (90%) O 84% 2 O 85, R = Ph 305b, R = Ph (92%) 306b, R = Ph (95%) toluene or O OEt OH EtOAc (90%) 312 $ e 313 Scheme 55. Reagents/conditions: (i) NiCl2 6H2O, NaBH4, MeOH H2O; (ii) Pd-C, EtOH $ 312 NH2OH HCl, NaOAc; (iii) SO2Cl, MeOH. 94%

O O O D O 6. Tandem [5 2] cycloaddition of oxidopyrylium species H EtOH 311 2 313 D Pd-C and [4 2] cycloadditions O +O EtOH O HO Mascarenas and co-workers have also developed a novel 312 and efﬁcient method for the synthesis of 6,7,5-tricarbocyclic Scheme 57. systems having a 1,4-oxa bridge in the seven-membered ring via an intramolecular thermal [5Cþ2C] pyroneealkene cyclo- Recently, Trivedi and co-workers reported transformations addition followed by a DielseAlder reaction in tandem.69 of the dimer 311 to highly functionalized oxa-bridged cyclo- Thus, heating the pyranones 307 and 309 in the presence of octanoids and other interesting carbocyclic systems.73 Thus, an appropriate 1,3-diene at 160 C afforded the carbocycles it was observed that hydrogenation of the dimer 311 in ethanol 308a,b and 310a,b with a well-deﬁned stereochemistry did not give the expected dihydro product 312, the compound (Scheme 56).69 The overall sequence constitutes an intramo- 313 was obtained instead. When the reaction was performed in lecular [5þ2] pyroneealkene cycloaddition followed by an non-nucleophilic solvents such as ethyl acetate, however, it intermolecular DielseAlder reaction.69,70 yielded the expected dihydro product 312 (Scheme 57). 3421

Treatment of 312 with PdeC in the presence of ethanol also 318 from the diazo ketone 317 and cycloaddition with prop- gave the product 313. Apparently, the product 312 undergoes argyl bromide gave the adduct 319 in excellent yield. Reduc- a transannular reaction, leading to the oxonium ion intermedi- tion of 319 gave the ketone 320, which upon transformation ate that, upon interception with ethanol, gives the compound into a silyl enol ether followed by ozonolysis furnished cis- 313 (Scheme 57). nemorensic acid 321 (Scheme 60). Epoxidation of the adduct In order to further explore the synthetic potential, the dihy- 319 with dimethyldioxirane gave the epoxide 322, which was dro product 312 was reduced with sodium borohydride and converted into the olefinic alcohol 323. Further transformation alkylated with benzyl bromide to give the dibenzyl ether of 323 gave the target 4-hydroxy-cis-nemorensic acid 325, via 314. Hydration of the pyranyl ether 314 in the presence of 324 (Scheme 61).76a Hodgson and Le Strat have also reported an acidic resin such as Dowex 50W-X4 gave the aldehyde the synthesis of 3-hydroxy-cis-nemorensic acid and nemoren- 315 containing a bridged eight-membered ring (Scheme sic acid employing the cycloaddition of the carbonyl ylide 318 58).73 Thus, the dimerization of 3-oxidopyrylium reported with allene.76b The details of these studies and preliminary re- by Hendrickson and Farina72 and the studies presented herein sults on the enantioselective cycloaddition have appeared constitute a potentially useful method of transforming furans recently.76c into functionalized cyclooctanoids, which are present in 74,75 many natural products. Br O Me Me i Me O O OBn O+ O O - O O O Me OHC N Me 318 i, ii iii O 2 317 319 ii Me OBn O O BnO Me Me BnO HO 315 O 312 314 Me Me iii, iv Me COOH Scheme 58. Reagents/conditions: (i) NaBH , MeOH, 10 C, 68%; (ii) NaH, O O 4 COOH 321 O Me benzyl bromide, Bu4Nl, THF, 77%; (iii) Dowex 50W-X4, LiBr, aq MeCN, cis-nemorensic acid 320 88%. Scheme 60. Reagents/conditions: (i) Rh2(OAc)4, propargyl bromide, CH2Cl2, e In this context, it may be mentioned Mascarenas and co- rt, 84%; (ii) H2,Pd C, MeOH, 92%; (iii) LDA, THF, 78 C, TMSCl, 90%; (iv) O /O ,CHCl , 78 C, then 35% H O , 88% HCOOH, 100 C, 97%. workers23a reported that the adduct 111, obtained by the cyclo- 2 3 2 2 2 2 addition of the oxidopyrylium derived from 57 (vide infra; Scheme 11) and cyclopropenone acetal, may be transformed Br Br OH into cyclooctanoids of the type 316. Thus, the reduction of O i Me the carbonyl group and subsequent ring opening of the cyclo- Me Me ii e O O propane ring in the presence of Ac2O TMSOTf gave the O O Me 323 O Me O Me compounds 316a,b (Scheme 59). 319 322 iii Me OH HO Me Me O AcO Me Me H O i, ii R COOH O O O Me 324 O H O COOH 325 O O OAc 4-hydroxy-cis-nemorensic acid Me Me Me 111 OAc Me 316a, R = H Scheme 61. Reagents/conditions: (i) dimethyldioxirane (0.1 M in acetone), 316b, R = COMe CH2Cl2, rt, 94%; (ii) Zn, MeOH, 6, 97%; (iii) H2, [Ir(cod)py(Pcy3)]PF6, CH2Cl2, 93%. Scheme 59. Reagents/conditions: (i) NaBH4, CaCl2, 93%; (ii) Ac2O, TMSOTf, 316a (35%), 316b (34%). In continuation of their earlier studies on enantioselective cycloaddition, the authors also developed a catalytic enantioselective version of the inter- and intramolecular cycloaddi- 8. Rhodium-catalyzed generation of carbonyl ylides and tions of carbonyl ylides.77 Thus, in situ generation of the their cycloadditions carbonyl ylide from a precursor of the type 326 in the presence of catalysts 329/330 and cycloaddition of the resulting car- Rhodium-catalyzed generation of carbonyl ylides and their bonyl ylide with various alkenes was examined.77a The reac- cycloaddition is a vast and rapidly growing field. In view of the tion of 326 and norbornene in the presence of the catalyst recent reviews on this subject,6,7 we have made attempts to 330 gave the adduct 328, via 327, in maximum enantiomeric present some of the latest results in this area. excess (92%) (Scheme 62). Norbornadiene also underwent Hodgson and co-workers have extensively examined inter- an efficient cycloaddition to give the corresponding adduct as well as intramolecular cycloaddition of carbonyl ylides.76,77 in good enantiomeric excess.77a Cycloadditions in the pres- The intermolecular cycloaddition methodology was applied to ence of 329 as a catalyst generally gave a low enantiomeric the synthesis of nemorensic acid and 4-hydroxynemorensic excess. Several other catalysts were developed and their acid (Scheme 60).76a Thus, generation of the dipolar species efficacy in the enantioselectivity was examined.77b 3422

O Me Me Rh cat. O norbornene N Rh O O N2 O + - O Me SO2 O t 327 COOtBu 326 COO Bu COOtBu 328 cat. 330, C H -15 °C , 12 25 4 92% ee 329

330 Me Me C12H25 hexane O -15 °C O ORh N O O 2 COOtBu O P O ORh 331 COOtBu (+)-332 53%, 80% ee C12H25 330 4

Scheme 62.

Enantioselective intramolecular cycloaddition employing the O O aforementioned catalysts was also examined.77cef Thus, the N2 O + Rh2(OAc)4 in situ generation of the carbonyl ylide from the precursor O Me OHC O 331 in the presence of catalyst 330 gave the adduct 332 with 338 340 95% good enantiomeric excess (Scheme 62). Cycloadditions of var- 339 Me ious other analogues of 331 in the presence of both catalysts Scheme 64. were examined. In general, the catalyst 330 gave better results.77c Most recently, the authors have reported a tandem cross-metathesis/carbonyl ylide generationecycloaddition, Treatment of the diazo ketones of the type 338 with rhodium leading to a quick access to various types of polycyclic acetate and subsequent reaction with an aromatic aldehyde systems.77d,e 339 led to the dioxa-bridged compound 340 in excellent yield. Muthusamy and co-workers have reported extensive work Various aromatic aldehydes were found to undergo efﬁcient on the cycloaddition of various types of carbonyl ylides with cycloaddition to furnish adducts in excellent yields.78d a diverse array of dipolarophiles and have developed routes In continuation of their pioneering studies on carbonyl to a number of polycyclic frameworks.78,79 Recently, the au- ylide cycloaddition, Padwa and Mejia-Oneto recently reported thors have reported the cycloaddition of carbonyl ylides with intramolecular cycloadditions of pushepull diploes that led to imines, leading to oxa-bridged piperidinones (Scheme 63).78a complex molecular structures related to alkaloids.80a Thus, the Thus, the reaction of diazo ketones 333 and 336 with tosyl- reaction of the diazo ester 341 with rhodium(II)acetate gave imines 334 in the presence of rhodium acetate furnished the the pentacyclic compound 343, via the ylide 342, in excellent corresponding adducts 335 and 337, respectively, in good yield (Scheme 65). Similarly, the indolyl analogue 344 gave yields (Scheme 63). The same workers have also reported the compound 345 in excellent yield. the cycloaddition of carbonyl ylides with carbonyl groups, leading to dioxa-bridged compounds (Scheme 64).78d O O O N N N Rh2(OAc)4 Me OO O Ts Ts Me Et O+ Et O N Rh2(OAc)4 Et N + N N2 2 O Me O − O O Me 343 Me Me O COOEt COOEt R2 R2 341 COOEt 342 R1 (95%) 334 335 333 R1 O O R1 = H, R2 = Ph (74%) R = H, R = 4-FC H (64%) N 1 2 6 4 N Rh2(OAc)4 N O O Ts N O O Et N Ts Et Me N2 O + Rh2(OAc)4 N Me N2 O Me O 345 COOEt Me 344 R2 R1 R2 O COOEt (92%) 336 337 R1 Scheme 65. R1 = H, R2 = Ph (71%) R1 = COOEt, R2 = Ph (60%) Interestingly, in the reaction of the homologue 346, the re- Scheme 63. sulting carbonyl ylide added to the indole double bond to give 3423 the compound 347 (Scheme 66). In order to check the gener- Recently, Hashimoto and co-workers also reported the syn- ality of this cycloaddition across the p-bond of the ﬁve-mem- thesis of polygalolides in which the carbonyl ylide cycloaddi- bered ring, the reactions of several other substrates without tion was used as a key step to create the bridged polycyclic a vinyl tether were examined. Thus, the precursors 348 and framework.81b Thus, the diazo compound 358 upon treatment 349 underwent a similar cycloaddition upon treatment with with Rh(II)acetate generated the carbonyl ylide 359 that un- rhodium acetate to give the corresponding adducts 350 and derwent intramolecular cycloaddition to give the tricyclic 351, respectively (Scheme 67).80a The ligand effect on such compound 360, which upon selective removal of the protect- types of cycloaddition was also examined.80b ing group gave the alcohol 361. The alcohol 361 was elaborated into 362, which was subsequently transformed into O O polygalolide A via reaction with the aromatic aldehyde 363 81b N N and creation of the double bond (Scheme 69). Rh2(OAc)4 N O Et O Et N2 N O Me O OPMP Me OTBDPS 346 COOEt COOEt 347 N O i + (95%) 2 – O OPMP O OTBDPS Scheme 66. O O O 358 359

OPMP O OH O N O Rh (OAc) N O 2 4 OTBDPS OTBDPS ii O X O O O Et O 360 (73%) N O Et 2 O 361 X O COOR COOR O O 348, X = NMe, R = Me 350, X = NMe, R = Me (95%) MeO 349, X = O, R = Et 351, X = O, R = Et (90%) H H iii-v H O O Scheme 67. O MeO CHO HO O O O 363 O 362 OAc polygalolide A O Hashimoto and co-workers employed a carbonyl ylide cycloaddition as a key step for the synthesis of zaragozic acid Scheme 69. Reagents/conditions: (i) Rh2(OAc)4, PhCF3, 100 C, 73%; (ii) 81 (NH4)2Ce(NO3)6, Py, aq MECN, 91%; (iii) LDA, ZnCl2, THF, 78 C, 363, C, a squalene synthase inhibitor. The diazo ester 353 was then AC2O, 0 C; (iv) SiO2,CH2Cl2; (v) NaHCO3, aq MeOH, 18% (three prepared from the diester 352 in several steps. Treatment of steps). the diazo ester 353 with Rh(II)acetate in the presence of ace- tylacetylene gave the adduct 355 via cycloaddition of the car- Chiu and co-workers developed an intramolecular cycload- bonyl ylide 354 in excellent yield (Scheme 68). Osmylation of dition of a carbonyl ylide with an allene that led to annulated the double bond gave the diol 356, which was elaborated into 82a 81a oxa-bridged bicyclo[3.3.1]nonane ring systems and have zaragozic acid C 357 after a series of transformations. also described an enantioselective total synthesis of pseudolaric acid A, a biologically active principle of the Chinese O herb tujinpi (Scheme 70).82b Thus, the diazo ketone 364 OH COMe N O OMOM + upon treatment with a chiral rhodium catalyst gave the adducts R 2 i R _ O R OTBDPS R R 365 and 366 having 366 as the major product. Compound 366 OH O OMOM 352 TMSO R was transformed into the lactone 367, which upon acetylation 353 TMSO OTBDPS 354 furnished pseudolaric acid A 368. R = COOtBu O Molchanov and his group have examined the cycloaddition HO Me HO COMe of carbonyl ylides with cyclopropenes that led to cyclopropane R ii R OMOM 83a,b O O annulated oxa-bridged bicyclic systems. Thus, treatment of R OMOM R O O diazo ketones of the type 369 with rhodium acetate generated OTBDPS TMSO TMSO OTBDPS species of the type 370, which underwent cycloaddition with 356 355 (72%) cyclopropenes to give the corresponding adducts 371 in good O 83a Ph(CH2)3 yields (up to 84%) (Scheme 71). They also examined the O OH Me OAc cycloaddition of carbonyl ylides 372 and 373 and the role of HOOC O Ph 3-substituents in cyclopropenes on the stereochemistry of HOOC 83b O Me cycloaddition and other electronic effects. Recently, the au- HO COOH 357 thors have also reported the cycloaddition of the dipolar species

Scheme 68. Reagents/conditions: (i) Rh2(OAc)4, PhH, reﬂux, 72%; (ii) OsO4, 370 with methylene cyclopropanes and bicyclopropylidene, 83c NMO, aq acetone, 88%. which gave the corresponding adducts in good yields. 3424

OPMB OPMB

PMBO O O O O O Rh2{(S)-bptv}4 CHN2 H + H PhCF3 H Me O -40 °C O O O O 32% O 51% 366 O 364 365

O O O O AcCl Me Me Me Me DMAP OAc HOOC OH HOOC H H 368 (80%) 367 pseudolaric acid A

Scheme 70.

H R type 379 via the intermediate 378 (Scheme 72). Recently, O O O Ph the authors have also reported the generation of 1,3-dioxo- CHN Rh2(OAc)4 - Ph Ph H Ph 2 O lium-4-olates from acyloxy ketenes and their reaction with CH Cl O R 84b O 2 2 + Ph various p-partners. 369 rt Ph Ph Hu and co-workers recently reported a multicomponent 370 371 Rh(II)acetate catalyzed 1,3-dipolar cycloaddition of methyl O O R = H, Me, vinyl, phenyl - phenyldiazoacetate 380 with differentially activated carbonyl - O+ groups of aromatic aldehydes 381 and 382 that led to the for- O+ mation of triaryl-1,3-dioxolanes 383 and 384 in good-to-excel- 372 OMe 373 lent yields (Scheme 73).85a Thus, the decomposition of methyl Scheme 71. phenyldiazoacetate in the presence of p-anisaldehyde and p-nitrobenzaldehyde gave the dioxolanes 385 and 386 84 Hamaguchi and co-workers have examined the generation (45:55) in 50% yield (Scheme 73), along with minor amounts of carbonyl ylides (and their conversion into acyloxy ketenes) of the corresponding epoxides derived from the reaction of al- and their reaction with various p-partners. They observed that dehydes. Interestingly, the electron-rich aldehydes participated mesoionic 1,3-dioxolium-4-olates (generated by a Rh2(OAc)4- in the formation of carbonyl ylides. None of the oxolanes catalyzed decomposition reaction of diazophenylacetic anhy- formed from the diazo compound with the same two alde- dride derivatives) undergo ring opening into acyloxy ketenes hydes. Application of this methodology for the synthesis of that give [2þ2] cycloadducts with various ketenophiles. tRNA inhibitor analogues was also reported.85b Only in one case, i.e., reaction of 374 in the presence of Rh (OAc) and cyclopentadiene, did the resulting dipolar spe- 2 4 O cies 375 gave the adducts 376a,b as the major products and Ph Ph COOMe COOMe Ar1 H 377 as the minor product (Scheme 72). Reaction of the dipolar Ar2 O Ar N2 381 Rh2(OAc)4 + 2 O species in the presence of dihydrofuran gave adducts of the + O O CH2Cl2 O Ph COOMe Ar 1 Ar1 380 383 Ar2 H 384 Ar Ar 382 N2 O + Ar Rh2(OAc)4 O Ar = electron-rich aromatic ring O O - 1 R O O Ar = electron-poor aromatic ring O 2 O R 378 R 375 O 374 Ph COOMe O COOMe Ph O O O Ar O Ar O O O N OMe O Ar O OMe 2 O O2N O O R O 385 386 O + R O R 376a p 379 376b, Ar = p-NO C H , Ar = -NO2C6H4 Scheme 73. 2 6 4 Ar = p-NO C H , p R = p-ClC H (55%) 2 6 4 R = -ClC6H4 (24%) 6 4 R = p-ClC6H4 (86%) p + Ar O Ar = -NO2C6H4, R = p-MeOC H (90%) Greene and co-workers recently reported the synthesis of 377 p 6 4 O R , Ar = -NO2C6H4, many natural products such as mappicine ketone and campto- p O R = -ClC6H4 (21%) thecinoids that employed annulated hydroxy pyridones as pre- Scheme 72. cursors, which were prepared by cycloaddition of carbonyl 3425

O O O OH N SO Ph Rh (OAc) N N 2 2 4 Me N N O 2 COOMe COOMe O 387 388 (81%) 389

Scheme 74.

Me Me Me N N N O O O N2 Rh2(O2CC7H15)4 O - O OMe OMe PhH O OMe + O O N O 50 °C O N O 74% N O

392 391 OTBS 390 OTBS OTBS

O N H Rh (O CC H ) N 2 2 7 15 4 Me O O O O O H PhH H 50 °C O N N Me N N OTIPS H 73% N2 OTIPS O 393 394

Scheme 75. ylides.86 In one example, the hydroxypyridone 388, prepared and functionally complex natural products. Moreover, asym- by cycloaddition of the carbonyl ylide derived from 387 metric versions of the aforementioned cycloadditions provide with methyl acrylate,87 was used for the synthesis of mapp- access to enantiomerically pure/enriched compounds. The icine ketone 389 (Scheme 74),86a and camptothecin.86bed cleavage of the oxa-bridge in the cycloadducts is one of the Schreiber and Okuri have developed a remarkable strategy important steps in the manipulation. Although there are involving carbonyl ylide cycloaddition that efficiently leads to some existing methods, the development of an alternative complex molecular architectures via a folding pathway.88 more efficient methodology would further enhance the syn- Thus, the diazo ketone 390 on treatment with Rh(II)octanoate thetic potential of cycloadducts. The studies presented in this gave the compound 392, via cycloaddition in the species 391. report provide a deeper insight into mechanistic, and regio- Similarly, treatment of the diazo ketone 393 with Rh(II)octa- and stereochemical aspects of the cycloadditions, which may noate also furnished the compound 394 in good yield having enable the design of new precursors for cycloaddition that an alkaloid-like framework (Scheme 75).88 would generate molecular structures of greater complexity in an efficient manner. Moreover, it would be desirable to develop an organo-catalytic method for the generation of oxido- 9. Concluding remarks pyrylium/carbonyl ylides and their cycloaddition. It is evident from the above discussion that cycloaddition of oxidopyrylium species both from pyranulose acetate and from Acknowledgements hydroxypyrones has evolved into a powerful methodology for the creation of diverse molecular frameworks having an oxa- Continuing financial support to V.S. from the Department bridge that are not readily available otherwise. The presence of Science and Technology, New Delhi, is gratefully acknowl- of an oxa-bridge and other functionalities permits further edged. G.K.T. thanks UGC New Delhi for a research grant. manipulation of the cycloadducts into various types of functionalized carbocyclic systems related to different classes of References and notes natural products. This methodology has led to the total synthesis of complex natural products in regio- and stereoselective 1. (a) Chanon, M.; Barone, R.; Baralotto, C.; Julliard, M.; Hendrickson, J. B. fashion. Similarly, the cycloaddition of carbonyl ylides de- Synthesis 1998, 1559e1583; (b) Corey, E. J.; Cheng, X.-M. The Logic of rived from rhodium-catalyzed reactions of diazo ketones pro- Chemical Synthesis; John Wiley and Sons: New York, NY, 1989. 2. Sammes, P. G. Gazz. Chim. Ital. 1986, 119, 109e114. vides a more flexible and general methodology for the 3. (a) Katritzky, A. R. Chem. Rev. 1989, 89, 827e861; (b) Ohkata, K.; synthesis of a diverse array of molecular structures and has Akiba, K. Y. Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; been employed as a key step in the synthesis of structurally Academic: New York, NY, 1996; Vol. 65, pp 283e374. 3426

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Biographical sketch

Vishwakarma Singh was born in Bijaikaf, UP, India and obtained his Ph.D. Urlam Murali Krishna was born in India, received his M.Sc. degree in or- degree from University of Gorakhpur under the supervision of Professor S. ganic chemistry from Andhra University in 1998. He joined the research group Giri. He continued his scientiﬁc education as a senior research fellow of Prof. Girish Trivedi at Indian Institute of Technology (IIT) Bombay and re- (CSIR, New Delhi) in the direction of Professor Goverdhan Mehta at the In- ceived his Ph.D. degree in 2004 for his work on asymmetric dipolar cycload- dian Institute of Technology, Kanpur and University of Hyderabad. He was ditions of 3-oxidopyrylium ylides. Immediately thereafter he joined Professor awarded a Monbusho fellowship from the Ministry of Education, Government Timothy Snowden’s laboratory at the University of Alabama, U.S.A. where he of Japan, to work with Professor E. Osawa at Hokkaido University, Sapporo, worked as a postdoctoral associate on the development of novel asymmetric Japan (1979e80). He then moved to United States, and worked with Professor routes to the total synthesis of xenia diterpenoid natural products. In 2006, A. R. Martin at University of Arizona (1980e81) and Professor James B. Hen- he moved to Emory University School of Medicine where he is working on drickson at Brandeis University (1981e82). Dr. Singh returned to India and the design and modiﬁcation of biomaterials employing bioorthogonal chemi- after working at Malti-Chem Research centre, Nandesari, Baroda (1982e84) cal strategies under the supervision of surgeon and Professor Elliot Chaikof. and M. S. University Baroda (1984-89), he moved to Indian Institute of Tech- His research interests include total synthesis of complex natural products, syn- nology Bombay and continuing as a Professor of Chemistry. He is the recipient thetic methods development, and bioconjugate chemistry. of several endowment awards. He is a fellow of the Indian National Science Academy (INSA), New Delhi. His research interests are in the area of synthetic organic chemistry and organic photochemistry.

Vikrant was born in Agra, Uttar Pradesh, India. He obtained his B.Sc. (Hons.) Girish K. Trivedi worked at National Chemical Laboratory Pune, under the and M.Sc. degrees from Banaras Hindu University, Varanasi, Uttar Pradesh. supervision of Dr. S. C. Bhattacharya and obtained his Ph.D. degree from Currently, he is pursuing his Ph.D. as senior research fellow at the Department Poona University. He joined Indian Institute of Technology Bombay in 1966 of Chemistry, Indian Institute of Technology Bombay, under the supervision of as associate lecture and he became Professor of Chemistry in 1980. He also Professor Vishwakarma Singh. His research interests are in the area of organic worked as a Research Associate with Professor K. Nakanishi at Columbia Uni- synthesis. versity, New York (1977e78). His research interests are in the area of essential oils and development of new synthetic methodology and synthesis. Currently, he is an Emeritus Professor in the Department of Chemistry, IIT Bombay.