1,3-Dipolar cycloaddition reactions are among the most powerful methods in organic synthesis.1 A particularly attractive feature is their ability to rapidly increase molecular complexity and lead to a high degree of functionality. These unique reactions were extensively studied by the Huisgen group starting in the early 1960's and their rate and regioselectivity can be understood through FMO analysis.2 – 4 (3+2) Cycloadditions are also extremely useful for the synthesis of natural products, pharmaceutical agents, and other biologically important structures employing rather simple starting materials. Dipolar cycloadditions using chiral substrates for asymmetric synthesis have been extensively explored since the 1990's.5 Several reviews and articles have been published dealing with enantioselectivity aspects of dipolar cycloaddition chemistry,6 – 8 therefore this minireview is intended to provide a selective rather than an exhaustive survey of the enantiospecific chemistry of some of the more common 1,3-dipoles, reported over the past several years.

Diazoalkanes

In recent years, the development of catalytic asymmetric methods has proved to be quite fruitful and the use of diazoalkane cycloadditions has garnered a lot of interest. For example, the Maruoka lab demonstrated that titanium BINOLate complexes promote an enantioselective cycloaddition of diazoacetates to acrolein derivatives with modest yield but good to excellent enantioselectivity. Thus, the addition of t-butyl diazoacetate (1a) with 2-methyl-propenal (2a) was promoted by 10 mol % of a 2:1 (S)-BINOL:Ti(Oi-Pr)4 complex to give the 4,5-dihydro-1H-pyrazole derivative 3a in 52% yield and with 91% enantiomeric excess (Scheme 1).9 Under similar catalytic conditions, the reaction of diazoacetate 1a with 2-substituted propenal 2b afforded dihydropyrazole derivative 3b in 63% yield and with 82% ee, and the reaction of diazoacetate 1a with 2-substituted propenal 2c furnished the dihydropyrazole 3c in 82% yield and with 92% ee. This methodology was applied to the enantioselective synthesis of manzacidin A (7). In this example, catalytic amounts of bis{((S)-binaphthoxy)(isopropoxy)titanium} oxide mediated the cycloaddition of ethyl diazoacetate (1b) with 2-methyl-propenal (2a) to give dihydropyrazole 3d in 52% yield and with 95% enantiomeric excess. The reduction of the aldehyde functionality in intermediate 3d by the action of NaBH4 and reaction of the resulting alcohol with methyl orthoformate under acidic conditions gave the bicyclic compound 4 in 65% yield over two steps. Exposure of compound 4 to H2 on Raney nickel provided an 85:5 mixture of the recyclized compound 5 and an epimer at the indicated carbon. This diastereoselectivity is attributed to the epimerization of the ester followed by selective lactonization and hydrolysis rather than a selective reduction. Finally, reaction of the alkoxide anion derived from compound 5 with trichloromethyl ketone 6 furnished the chiral product 7 in 50% yield from the bicyclic intermediate 4.

scheme 1

Scheme 1

Building upon Maruoka's work, Ryu's group explored the use of chiral oxazaborolidinium ion 8 to catalyze the cycloaddition of diazoacetates with acrolein derivatives.10 In this case, catalyst 8a (20 mol %) mediated the cycloaddition of diazoacetate 1b with acrolein derivative 2a to give the dihydropyrazole 3d in 87% yield and 91% ee (Scheme 2). Likewise, the reaction with acrolein derivative 2c produced the dihydropyrazole 10a in 97% yield and with 92% ee. In both of these cases, the enantioselectivities were similar to those in experiments involving Maruoka's BINOLate catalyst, but the yields were significantly improved. In the case where R1 = Bn (compound 9a), the use of catalyst 8a led to the isolation of dihydropyrazole 10b in 72% yield, but with only 76% ee. Alternatively, the use of catalyst 8b improved the enantioselectivity, producing the dihydropyrazole 10b in 72% yield and 91% ee. Disubstituted acrolein derivatives also performed well. Dimethylacrolein (9b), for example, reacted with ethyl diazoacetate (1b) in the presence of compound 8a to give compound 10c in 93% and with 92% ee. The cyclopentenyl carbaldehyde 9c reacted to give dihydropyrazole 10d in 73% yield and with 97% ee, while the cyclohexenyl carbaldehyde 9d afforded dihydropyrazole 10e in 75% yield and in 92% enantiomeric excess.

scheme 2

Scheme 2

Sibi and coworkers used chiral magnesium complexes to promote the enantioselective addition of ethyl diazoacetate (1b) to electron-deficient alkenes.11 The reaction of ethyl diazoacetate with alkene 11a in the presence of Mg(NTf2)2 and ligand 12 at –20°C produced the dihydropyrazole 13a in 72% yield with 99% ee (Scheme 3). A variety of α,β-unsaturated amides gave good yields and excellent enantiomeric excess. The reaction with fumaric acid derivative 11b, which contains a second carbonyl conjugated to the double bond of dipolarophile, gave dihydropyrazole 13b in 91% yield and 99% ee under similar conditions, while the more sterically demanding alkene 11c reacted with the magnesium complex of ligand 12 at room temperature to provide the dihydropyrazole 13c in 79% yield and 98% ee. An aryl-substituted compound also gave good chemical yield, though the enantioselectivity was somewhat lower. The magnesium complex-mediated reaction of cinnamic acid derivative 11d with ethyl diazoacetate (1b) at 40°C furnished the product 13d in 76% yield with good 88% ee. More highly substituted alkenes were also reactive, although the yields were significantly reduced. Ethyl diazoacetate (1b), for example, reacted with alkene 14 to afford product 15 in 61% yield but with 99% ee.

scheme 3

Scheme 3

After considerable experimentation, the Suga group found conditions that employ chiral Ni(II) catalysts to facilitate enantioselective cycloadditions.12 The substrates that worked best were the same general pyrazolidinone derivatives used in Sibi's work.11 Ethyl diazoacetate (1b) added to acrylamide 11a in the presence of a complex formed between Ni(BF4)2·6H2O and ligand 16a at –45°C to give a mixture (85:15) of product 13a and isomer 17a in 87% yield (Scheme 4). The stereoselectivity of the reaction was excellent, with the product 13a being produced with 97% enantioselectivity. Alternatively, reaction of acrylamide 11e with ethyl diazoacetate (1b) mediated by the nickel complex with ligand 16b at room temperature produced only the isomer 13e in 94% yield with 93% ee. The use of the catalyst derived from ligand 16a also promoted the reaction, although in slightly diminished yield (87%). The counterion of the Ni(II) complex also affected the enantioselectivity, with BF4 – generally giving better results. In the case of fumaric acid derivative 11f, however, the reaction with ethyl diazoacetate (1b) was best promoted using Ni(ClO4)2 to form the catalytic complex with ligand 16b, furnishing dihydropyrazole 13f in 92% yield and 85% ee. Importantly, substituted α-diazoacetates also produced cycloadducts. The reaction of ethyl diazoacetate (1b) with acrylamide 11a in the presence of ligand 16a and Ni(ClO4)2 gave compound 19a in only 15% yield and 70% ee, the remainder of the products were related to a cyclopropane and an alkene derived from the cycloadduct. Other catalyst complexes increased the yield (up to 40%) at the expense of enantioselectivity. In contrast, the substituted diazoacetate 18b gave product 19b in 73% yield and 75% ee under similar conditions.

scheme 4

Scheme 4

Nitrones

Cycloaddition between the zinc salts of allylic alcohols and various electron-poor nitrones produced isoxazolidines in good yield with excellent enantioselectivity in the presence of diisopropyl tartrate (DIPT).13 For example, the cycloaddition reaction of allyl alcohol (20a) with nitrone 21 under the conditions specified in Scheme 5 gave isoxazolidine 23a in 69% yield and with 98% ee. Under similar conditions, 2-buten-1-ol (20b) reacted to give 64% yield of isoxazolidine 23b with >99% ee, although in this case it required more equivalents of reagents to induce reaction with nitrone 21. Alcohols 20c,d afforded isoxazolidines 23c,d with >99% ee (48% yield) and 97% ee (63% yield), respectively.

scheme 5

Scheme 5

Another interesting cascade involving nitrones is the copper-catalyzed reaction with alkynes producing β-lactams that was originally reported by Kinugasa.14 Stoichiometric amounts of copper(I) phenylacetylide (24) reacted with various aryl nitrones 25 in pyridine and gave β-lactams 26 in 50–60% yield (Scheme 6). In each case, only the cislactams were isolated.

scheme 6

Scheme 6

Miura and coworkers showed that the reaction could also be carried out using catalytic amounts of CuI in the presence of pyridine.15 Asymmetric reactions were reported to occur with chiral bisoxazoline ligands producing β-lactams with moderate (40–68%) enantiomeric excess. The use of an oxazolidinone with a chiral auxiliary attached to the alkyne did provide enantiomerically pure products.16 In all of these latter reports, mixtures of cis- and trans-lactam isomers were obtained in which the trans-product predominated. It was also shown that the cis-isomer could easily be converted to the trans-product when exposed to base.

The Fu group recently reported the use of C2-symmetric planar-chiral bis(azaferrocene) ligands for the catalytic enantioselective Kinugasa reaction.17 A variety of terminal alkynes 27 (R1 = Ar, Bn, 1-cyclohexenyl) were allowed to react with nitrones 28 (R2 = Ar, Cy, PhCO; R3 = Ar) in the presence of catalytic amounts of the CuCl·29 complex to give diastereomeric mixtures (>90:10) predominating in cis-substituted β-lactams 30 in moderate to good yields (45–90%) and with good enantiomeric excess (67–92%; Scheme 7). With regard to the R3 group on nitrone 28, electron-rich aromatic groups increased the enantioselectivity, although the yields were somewhat lower. An intramolecular variant of this catalytic enantioselective process was also reported. Nitrone 33 was converted to azetidinone 34 in the presence of the CuBr·35a complex in 74% yield and with 88% ee.18 Ligand 35b was also quite effective, providing compound 34 with 90% ee, though the yield was only 47%. The mechanism for the Kinugasa reaction14 is thought to involve a (3+2) cycloaddition of the nitrone with the respective copper acetylide to give isoxazolidine copper salt 31. Rearrangement of compound 31 then provided the copper enolate of the corresponding β-lactam (i.e., compound 32), which was subsequently protonated to provide the observed product. The proton source for this last step was most likely the conjugate acid of the base used to generate the copper acetylide. Through considerable experimentation, the Fu group developed conditions that allowed for the reaction of the enolate with added electrophiles. Thus, exposing starting material 36 to CuBr·35a in the presence of KOAc, allyl iodide, and the silyl enol ether of acetophenone gave rise to β-lactam 37 in 70% yield and with 90% ee (Scheme 8).18

scheme 7

Scheme 7

scheme 8

Scheme 8

Carbonyl ylides

The creation of carbonyl ylide dipoles from the reaction of α-diazo compounds with ketones through the intermediates 38 in the presence of Rh(II) catalysts (Scheme 9) has significantly broadened their applicability for natural product synthesis.19 – 28 The ease of generating the 1,3-dipole, the rapid accumulation of polyfunctionality in a relatively small molecular framework, the high stereochemical control of the subsequent (3+2) cycloaddition, and the fair predictability of its regiochemistry have contributed to the popularity of the reaction.29 , 30 When the reacting components are themselves cyclic or have ring substituents, complex multicyclic arrays, such as those contained in drugs and natural products, can be constructed in a single step.

scheme 9

Scheme 9

Recent developments over the past several years have shown that a number of catalytic asymmetric carbonyl ylide cycloadditions is possible.31 Hodgson and coworkers reported the first examples of enantioselective carbonyl ylide cycloaddition (up to 81% ee) using unsaturated α-diazo β-keto esters (Scheme 10).32 Because the catalystfree carbonyl ylide would be achiral, the observation of enantioselectivity provides unambiguous evidence for an enantioselective ylide transformation taking place via a catalyst-complexed intermediate (i.e., the complex 40).

scheme 10

Scheme 10

In a later report by this same group, the scope and generality of the catalytic enantioselective intramolecular tandem carbonyl ylide cycloaddition was further evaluated using a series of related unsaturated 2-diazo-3,6-diketo esters.33 The cycloadditions were found to proceed in moderate to good yields, with a difference in ee exhibited by the electronically different α-diazo keto esters used (Scheme 11). Values for ee up to 90% for alkene dipolarophiles and up to 86% for alkyne dipolarophiles were obtained.

scheme 11

Scheme 11

An evaluation of α-aryl-α-diazodiones in tandem intramolecular carbonyl ylide formation, enantioselective (3+2) cycloaddition, was also carried out by the Hodgson group.34 The substrates were designed to allow investigation of the electronic characteristics of the dipole upon asymmetric induction. Once again, electronic factors were found to play a key role in determining the outcome of the cycloaddition reactions with enantioselectivities of up to 97% ee (Scheme 12).35

scheme 12

Scheme 12

An efficient 15-step synthesis of the antimitotic alkaloid (−)-colchicine (50) involved a Rh-catalyzed transformation of α-diazo ketone 48 to produce an oxatetracyclic key intermediate 49 through an intramolecular (3+2) cycloaddition of an in situ generated carbonyl ylide dipole (Scheme 13).36 In this manner both the seven-membered rings B and C were formed in one step with concomitant installation of the oxygen functions in positions C-9 and C-10. Moreover, the intramolecular mode of the cycloaddition step permitted the use of an unactivated dipolarophile and thus allowed for the installation of the C-7 stereocenter prior to cycliation. The key cycloadduct 49 was obtained in 64% yield with high enantioselectivity (99% ee) and was easily converted to the alkaloid 50 in several additional steps.

scheme 13

Scheme 13

The Hashimoto group described a modified enantioselective protocol that uses chiral dirhodium(II) carboxylates to control the facial selectivity of the cyclization for assembling the pentacyclic ABCDE framework of the aspidosperma alkaloid family.37 Cycloaddition of the carbonyl ylide derived from indolyl-substituted diazoimides 51 under the influence of Rh2(S-TCPTTL)4 provided cycloadduct 53 in 43% yield and 66% ee with complete endo diastereoselectivity (Scheme 14). The undesired bicyclic epoxide 54 was also obtained in 42% yield as the other major by-product.

scheme 14

Scheme 14

Attempts to convert compound 54 into the cycloadduct 53 under the same conditions failed, leading the authors to hypothesize that the epoxide did not serve as an intermediate in the reaction. This system represents the first example of asymmetric induction in an intramolecular cycloaddition of a carbonyl ylide dipole across an indolyl π-bond.

Suga and coworkers have reported on a highly enantioselective 1,3-dipolar cycloaddition reaction between several 3-(2-alkenoyl)-2-oxazolidinones and carbonyl ylides that were generated from the Rh(II)-catalyzed reaction of N-diazoacetyl lactams of type 55. N-Diazoacetyl lactams that possess 5-, 6-, and 7-membered rings were transformed to the corresponding epoxy-bridged indolizidines, quinolizidines, and 1-azabicyclo[5.4.0]undecanes with good to high enantioselectivities according to this method. A regio- and stereoselective ring opening of the epoxy-bridged indolizidine cycloadduct 57 gave the corresponding alcohol 58 as a single diastereomer. The sequence of an asymmetric cycloaddition reaction followed by ring opening was applied to the syntheses of several chiral indolizidine derivatives, including (+)-tashiromine (59) (Scheme 15).38

scheme 15

Scheme 15

Saba and coworkers used proline-derived α-diazo compounds for the enantioselective synthesis of the indolizidine skeleton, notably creating a quaternary center adjacent to nitrogen.39 In this report, the α-diazo keto ester 60a was refluxed in toluene in the presence of Rh2(OAc)4 to give a mixture (60:40) of indolizidine 62a and the trans-stereoisomer in 84% combined yield, and the indolizidine 62a was produced with high enantioselectivity (80% ee) (Scheme 16). Subjecting benzyl ester 60b to the same reaction conditions produced a mixture in which the indolizidine 62b was the major diastereomer, while the diastereoselectivity increased to 72:28 and the product 62b was isolated with 84% ee. In both cases, the use of Cu(acac)2 led to slightly higher yields (90% in each case) but with a significant erosion in diastereoselectivity. Of particular interest was that the ammonium ylides 61a,b were isolable, and each was heated to produce product 62a,b with complete selectivity and with 95% ee. This provided further evidence of the stereoselective nature of the [1,2]-shift. A related reaction was also observed using α-diazo keto ester 63 producing the cyclized product 65 in 65% yield via ammonium ylide 64.40

scheme 16

Scheme 16

The Saba group also demonstrated that the [2,3]-rearrangement strategy could be used for the synthesis of azabicyclo-[6.3.0]undecane systems containing quaternary carbon atoms adjacent to the nitrogen atom.41 Proline derivative 66 reacted with catalytic amounts of Rh2(OAc)4 in refluxing toluene to give a 9:1 mixture of [2,3]:[1,2]-rearrangement products 67 and 68 in 72% yield (Scheme 17). Analysis of a Mosher's ester derivative suggested that the product 67 was formed with 98% enantiomeric excess.

scheme 17

Scheme 17

Azomethine ylides

The Oh research group examined the ability of copper complexes derived from brucine diol derivative 71 to effect a concerted (3+2) cycloaddition between azomethine ylide dipoles obtained from imines 69 and nitroalkenes 70 (Scheme 18).42 Schiff base 69a, obtained by the condensation of benzaldehyde and methyl glycine, reacted with β-nitrostyrene (70a) in the presence of 20 mol % each of Cu(OTf)2, ligand 71, and DBN to give endo adduct 72a as a single diastereomer in 97% yield and with 84% enantiomeric excess. Similarly, the adduct 72b was isolated in 92% yield and with 92% ee and adduct 72c was isolated in 92% yield and with 90% ee. The nitroalkene could be substituted with little impact on the diastereoselectivity or enantioselectivity as shown in Scheme 18. The presence of a methyl group in alanine derivative 69d reduced the yield slightly (76%) but the enantioselectivity was still excellent (94% ee). A stepwise reaction mechanism, wherein a conjugate addition of the reactive azomethine ylide to the nitroalkene occurs first, followed by a Mannich-like cyclization, was ruled out by studies that showed the second step of such a mechanism as too slow to account for the rate of the reactions catalyzed by the copper–71 complex.

scheme 18

Scheme 18

Fukuzawa and coworkers showed that AgOAc and ligand 73 promoted the reaction of imines 69 and β-nitrostyrenes 70 to give predominantly endo adducts 72 in good yields and excellent stereoselectivities (Scheme 18).43 For example, the adduct 72a was produced (94:6 dr) in 70% yield and with 96% ee. Pyrrolidines 72b,c,f were formed in 71–80% yields and with enantiomeric excesses ranging from 91% (compound 72f) to 97%. In these cases, the catalyst loading was only 5 mol %. Sansano and coworkers, however, demonstrated that ligand 74 together with either Cu(OTf)2 or Ag(I) salts in the presence of Et3N effected the cycloaddition, also at 5 mol % catalyst load, but with the opposite diastereoselectivity.44 For example, the imino ester 69a reacted with β-nitrostyrene 70a in the presence of AgOBn, ligand 74, and Et3N to give a 91:9 mixture of exo and endo diastereomers, this time favoring the product exo - 72a. The exo adduct was isolated in 88% yield and with >98% enantiomeric excess. Similar diastereoselectivities, yields, and enantioselectivities were observed for a variety of subsituted imino esters and nitroalkanes.

The cycloaddition reaction of methylene lactone 75 with imino esters 69 in the presence of CuBF4 and chiral bisphosphine 76 (3 mol % each) gave spirocycles 77a–d in good yields and with excellent enantioselectivity (i.e., 99% ee) (Scheme 19).45 Varying the electronics of the aryl substituent did not significantly affect the reaction. Alkylsubstituted imino esters participated in the cycloaddition, but the yields were poorer.

scheme 19

Scheme 19

Azomethine imines

Asymmetric cycloadditions of azomethine imines have also received considerable attention. Various metal complexes have promoted the formation of cycloadducts with good to excellent enantioselectivities, diastereoselectivities, and chemical yields. For example, Maruoka's group developed a three-component reaction wherein a mixture of hydrazide 78, aldehyde 79b, and alkyne 80a were reacted in the presence of CuOAc, Ph-pybox 81, diacid 82, and 4 Å molecular sieves to give >95:5 mixture of compound 83b and the corresponding alkyne addition product 84b in 95% yield and with 99% ee (Scheme 20).46 Under these conditions, various aldehydes successfully participated in the reaction, with aldehydes 79b–d giving mixtures (>95:5) favoring products 83b–d in 96, 87, and 92% yield, respectively, with 96, >99, and 88% enantiomeric excesses, respectively. Several substituted alkynes also provided similar mixtures (>95:5) in excellent yields and enantioselectivities (product 83e, 87% yield and 99% ee; product 83f, 94% yield, 96% ee). It is not yet entirely clear if these reactions are concerted or, as Kobayashi and coworkers demonstrated,47 they are stepwise addition/cyclization reactions.

scheme 20

Scheme 20

Sibi and coworkers reported an exo-selective cycloaddition of acrylamide 11a with compound 85a mediated by a copper complex containing ligand 86 that gave product 87a in 90% yield with an 88:12 diastereomeric ratio and with 94% ee (Scheme 21).11 Compound 85b reacted under similar conditions to give the product 87b in 79% yield and with 95% ee. The crotonamide 11e reacted with compound 85b to give product 87c as a single isomer in 77% yield but with only 67% ee. Crotonamide 11e failed to react with compound 85a, even with 100 mol % of the copper complex.

scheme 21

Scheme 21

Inomata, Ukaji, and coworkers developed asymmetric methods for adding azomethine imines such as 85b to allylic alcohols with good enantioselectivities48 , 49 and they expanded the methodology to the more challenging homoallylic alcohols. Magnesium alkoxide derived from 3-buten-1-ol (88a) reacted with compound 85b in the presence of (R,R)-DIPT to provide product 90a in 76% yield and with 93% enantiomeric excess (Scheme 22).50 Likewise, compounds 89a,b reacted to give products 90b,c in 72 and 87% yields, respectively, with 93% ee in each case. Azomethine imines derived from aliphatic aldehydes provided highly variable chemical yield and moderate to good enantioselectivity (63–83% ee). Under the standard conditions, the more highly substituted homoallylic alcohol 88b reacted with compound 85b to give product 90d in 78% yield and with 95% ee.

scheme 22

Scheme 22

Suga's lab examined the use of a Ni(II) complex to effect asymmetric azomethine imine cycloadditions. In one example, chloroform solutions of dipole 85a added to acrylimide 92 in the presence of Ni(II) and ligand 93, furnishing a 93:7 mixture of product 94a and its cis-isomer 95a in 93% yield and with 97% ee (Scheme 23).51 The electronic nature of the aryl group of the azomethine imine had little impact on the reaction. Compound 91a afforded an 80:20 mixture of products 94b and 95b, with the product 94b being produced with 90% ee. Alternatively, dipole 91b furnished products 94c and 95c (91:9 dr) in quantitative yield, with product 94c having 95% ee. Heterocyclic substituents were successfully deployed with dipole 91c returning mixtures predominating in product 94d (64:36 dr) in 83% yield and 95% ee. Reactions with alicyclic derivatives proceeded with diminished yield and enantioselectivity, with dipole 91d giving products 94e and 95e (82:18 dr) in 74% yield, but with product 94e being produced with only 74% ee. The sterically less demanding dipole 85b reacted under similar conditions to give good yields and diastereoselectivities, but with low enantiomeric excess.

scheme 23

Scheme 23

Organocatalysts are also effective promoters of azomethine imine cycloadditions. 1,3-Dipolar cycloadditions of cyclic enones remain challenging substrates for LUMO-lowering iminium-based catalysis. The Chen's group, however, used the cinchona alkaloid derivative 98 to promote the addition of dipole 85b with cyclic enone 97a in the presence of 2,4,6-triisopropylbenenesulfonic acid (TIPBA) to furnish product 99a in 89% yield and with 90% ee (Scheme 24).52 Variously substituted aryl groups, such as in dipoles 89a and 89b, also participated in the reaction with enone 97a, giving products 99b and 99c in 73 and 99% yields, respectively, and with 92% ee in both cases. The furyl-substituted dipole 96 reacted with enone 97a to give product 99d in 99% yield and 95% ee. The use of cyclopentenone 97b required 20 mol % of the catalysts, but it reacted with dipole 85a (see Scheme 21) to afford product 99e with 90% enantiomeric excess, although in a somewhat diminished yield (78%). Similarly, the seven-membered ring dipolarophile 97c underwent cycloaddition with dipole 89a in the presence of 10 mol % of catalyst 98 to give 76% yield of product 99f with 93% ee.

scheme 24

Scheme 24

Chen's group also examined the use of catalyst 100 to promote the exo-selective cycloaddition of dipole 85b with iminium ions derived from α,β-unsaturated aldehydes, that provided modest to good yields and good to excellent enantioselectivity (Scheme 25).53 Dipole 85b, for example, reacted with a mixture of aldehyde 101a (10 mol %) and TFA in aqueous THF to give an 81:19 mixture of diastereomers 102a (96% ee) and 103a in 85% yield. The use of longer-chain aldehydes led to somewhat diminished yields but excellent enantioselectivities, as demonstrated by the reaction of dipole 85b with 2-heptenal (101b) that yielded 85% of products 102b (94% ee) and 103b as an 85:15 mixture. As with other examples using this dipolarophile, varying the electronic nature of the aromatic substituent did not significantly affect the stereoselectivity of the reactions. Azomethine imine 89a reacted with the iminum ion derived from 2-heptenal (101b) and catalyst 99, to produce an 88:12 mixture of products 102c (92% ee) and 103c in 66% yield, and the dipole 89b reacted under similar conditions to afford an 83:17 mixture of products 102d (95% ee) and 103d in 77% yield.

scheme 25

Scheme 25

Wang and coworkers used chiral bis-phosphoric acid 105 to construct spirocyclic oxindoles 106a–d (Scheme 26).54 Reaction of dipolarophile 104a and dipole 85b in the presence of 10 mol % of catalyst 105 afforded the product 106a in 93% isolated yield with 98% ee. As with other reports, varying the electronic nature of the aryl substituent on the dipole (e.g., in compounds 89a,b or 96) did not significantly change the yields or enantioselectivities of the reactions. Neither did changing the substitution pattern on the oxindole dipolarophile. Compounds 104b,c underwent cycloaddition mediated by catalyst 105 to provide spirocyclic products 106b,c in 84 and 93% yields, respectively, with 96% ee in both cases. Similarly, the dipolarophile 104d reacted to give spiro compound 106d in 87% yield and with 99% enantiomeric excess.

scheme 26

Scheme 26

The impact of 1,3-dipolar cycloaddition chemistry is now well recognized in the fields of organic synthesis, drug discovery efforts, polymer chemistry, and materials science. By using chiral starting materials for the cycloaddition reactions, it is possible to completely control the enantioselectivity as well as regio- and diastereoselectivity. In recent years, steady progress has also been made in metal-catalyzed asymmetric dipolar cycloaddition chemistry. Forthcoming developments will also depend on gaining a greater understanding of the mechanistic details of this fascinating and synthetically important process.