Recent Advances of 1,3-Dipolar Cycloaddition Chemistry for Alkaloid Synthesisa

CHAPTER NINE

Recent Advances of 1,3-Dipolar Cycloaddition Chemistry for Alkaloid Synthesisa Albert Padwa1, *, Scott Bur2 1

Department of Chemistry, Emory University, Atlanta, GA, USA Department of Chemistry, Gustavus Adolphus College, St. Peter, MN, USA *Corresponding author: E-mail: [email protected]

2

Contents 1. Introduction 2. Carbonyl Ylides 3. Mesoionic Systems 4. Azides 5. Azomethine Ylides 6. Azomethine Imines 7. Nitrones 8. Nitrile Oxides 9. Asymmetric Reactions of 1,3-Dipoles 10. Concluding Remarks Acknowledgment References

242 242 247 256 263 271 275 284 289 300 300 300

Abstract The synthesis of heterocyclic compounds has attracted significant attention for decades. Among the various heterocycles isolated from nature, alkaloidal natural products have received significant attention due to their diverse bioactivity. As highlighted in this minireview, a growing area of interest in organic synthesis involves the use of substituted 1,3-dipoles for the preparation of different alkaloidal natural products. Cascade reactions proceeding by an intramolecular 1,3-dipolar cycloaddition chemistry are of particular interest to the synthetic organic community because of the increase in molecular complexity involved and the high isolated yields. The synthesis of numerous alkaloids has been elegantly accomplished in recent years using an assortment of synthetic dipole intermediates.

a

Dedicated with respect and affection to the memory of Professor Alan Roy Katritzky, University of Florida, Gainesville (August 18, 1928eFebruary 10, 2014).

Advances in Heterocyclic Chemistry, Volume 119 ISSN 0065-2725 http://dx.doi.org/10.1016/bs.aihch.2016.03.005

© 2016 Elsevier Inc. All rights reserved.

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Keywords: 1,3-Dipoles; Alkaloids; Asymmetric synthesis; Azides; Azomethine imines; Azomethine ylides; Carbonyl ylides; Cycloaddition; Mesoionic systems; Nitrile oxides; Nitrones

1. INTRODUCTION 1,3-Dipolar cycloaddition reactions are among the most powerful methods in organic synthesis (2003MI). 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 1960s (1963AGE565, 1984MI1), and their rate and regioselectivity can be understood through FMO analysis (1984MI407). [3þ2]-Cycloadditions are also extremely useful for the synthesis of natural products, pharmaceutical agents, and other biologically important structures employing rather simple starting materials. In addition, dipolar cycloadditions using chiral substrates for asymmetric synthesis have been extensively explored since the 1990s (2014MI175). Because several reviews and related articles have recently been published dealing with the synthetic aspects of dipolar cycloaddition chemistry (2007T12247, 2013MI133) for the preparation of natural products, this review chapter is intended to provide a selective rather than an exhaustive survey of the most useful 1,3-dipoles for alkaloid synthesis over the past several years.

2. CARBONYL YLIDES The creation of carbonyl ylide dipoles from the reaction of a-diazo compounds with ketones in the presence of Rh(II) catalysts (Scheme 1) (1998MI1, 1986CR919, 1994CR1091, 1991CR263, 1992T5385, 1996CR223, 2013MI133) has significantly broadened their applicability for natural product synthesis (1997JOC1317, 1993JOC7635, 1994TL9185). The ease of the generating the dipole, the rapid accumulation of

Scheme 1

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polyfunctionality in a relatively small molecular framework, the high stereochemical control of the subsequent [3þ2]-cycloaddition, and the fair predictability of its regiochemistry have contributed to the popularity of the reaction (1976AGE123, 2002T9477). 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. One of the early examples of the trapping of a carbonyl ylide dipole with an alkene for natural product synthesis is found as the central step of Dauben’s approach to the tigliane ring system (Scheme 2) (1993JOC7635). Carbonyl ylide 5, generated from the diazocarbonyl 4 in the presence of a catalytic amount of rhodium(II) acetate, underwent an intramolecular addition with the olefin to form the C6,C9-oxido-bridged tigliane ring system 6. The two new stereocenters at C8 and C9 were formed with the correct configurations relative to C14 and C15 presented by the natural tigliane compounds. The high stereospecificity in the ring closure reaction could be related to steric interactions or the introduction of conformational strain in the tether, which disfavors the transition state where the cyclopropane ring and the oxido bridge are on the same side of the molecule. A synthesis of the complex pentacyclic alkaloid ()-aspidophytine 11 using a related strategy was carried out making use of a domino dipole cascade sequence (2006OL3275, 2008HCA285). The key sequence of reactions involved a 1,3-dipolar cycloaddition of the “pushepull” dipole 8 across the indole p-system. The exo-cycloadduct 9 was the exclusive product isolated from the Rh(II)-catalyzed reaction of 8. It was assumed that in this case, the bulky tert-butyl ester functionality blocks the endo-approach thereby resulting in cycloaddition taking place from the less-congested exo face. Treatment of the resulting dipolar cycloadduct 9 with BF3$OEt2 induces a domino fragmentation cascade. The reaction proceeds by an initial cleavage of the oxabicyclic ring and formation of a transient N-acyliminium

Scheme 2

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Albert Padwa and Scott Bur

ion, which reacts further with the adjacent tert-butyl ester and sets the required lactone ring present in aspidophytine. A three-step sequence was then used to remove both the ester and OH groups from lactone 10. Subsequent functional group manipulations allowed for the high-yielding conversion of 10 into ()-aspidophytine 11 (Scheme 3). As a further extension of “pushepull” dipole cycloaddition chemistry, the Rh(II)-catalyzed cyclization/cycloaddition cascade was applied toward the hexacyclic framework of the kopsifoline alkaloids. The kopsifolines 14 are structurally intriguing compounds, related to and possibly derived from an aspidosperma-type alkaloid precursor 12. A possible biogenetic pathway to the kopsifolines from 12 could involve an intramolecular epoxide-ring opening followed by loss of H2O as shown in Scheme 4. The interesting biological activity of these compounds, combined with their

Scheme 3

Scheme 4

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fascinating and synthetically challenging structure, makes them attractive targets for synthesis. Using the metal-catalyzed domino reaction as a key step, the heterocyclic skeleton of the kopsifolines could eventually be built by a 1,3-dipolar cycloaddition of a “pushepull” carbonyl ylide dipole derived from a-diazo ketoester 15 across the indole p-bond. Ring opening of the resulting cycloadduct 16 followed by a reductive dehydroxylation step produced the critical silyl enol ether 17 necessary for the final F-ring closure. The facility and stereoselectivity of the key cycloaddition reaction was investigated in more detail using some model substrates. It was found that the heterocyclic skeleton of the kopsifoline alkaloid family 18 could readily be constructed by the proposed sequence of reactions outlined in Scheme 5 (2006OL5141, 2007T5962). The isolation of 16 as a single diastereomer was rationalized by recognizing that the indole moiety approaches the dipole from the least sterically encumbered position. Ring opening of the resulting cycloadduct 16 followed by a reductive dehydroxylation step resulted in the formation of the silyl enol ether 17 necessary for the final F-ring closure of the kopsifoline skeleton (i.e., formation of 18). The total synthesis of several members of the vinca and tacaman class of indole alkaloids has also been accomplished using “pushepull” dipoles in the critical cycloaddition step (2007OL3249, 2008JOC2792). The central step in the synthesis consists of an intramolecular [3þ2]-cycloaddition reaction of an a-diazo indoloamide (i.e., 19), which delivers the pentacyclic skeleton of the natural product in excellent yield (Scheme 6). The acid lability of

Scheme 5

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Albert Padwa and Scott Bur

Scheme 6

the oxabicyclic structure was exploited to establish the trans-D/E-ring fusion of ()-3H-epivincamine 22. Finally, a base-induced ketoamide ring contraction was utilized to generate the E-ring of the natural product. A variation of the cascade sequence of reactions used to synthesize ()-3H-epivincamine 22 was also employed for the synthesis of the tacaman alkaloid ()-tacamonine 23. In recent years, the Boger group has developed a new synthetic approach to the vinca alkaloids based on an intramolecular [4 þ 2]/ [3 þ 2] cycloaddition reaction of 1,3,4-oxadiazoles which proceeds through a “pushepull” dipole (2005OL4539, 2002JACS11292, 2006JACS10589, 2006JACS10596, 2006AGE620). This unique domino cascade assembles the fully functionalized pentacyclic ring system of vindoline 28 in a single step that forms four CeC bonds and three rings while introducing all the requisite functionality and setting all six stereocenters within the central ring including three contiguous and four total quaternary centers (Scheme 7). The reaction leading to 27 is initiated by an intramolecular inverse electron demand DielseAlder cycloaddition of the 1,3,4-oxadiazole 24 with the tethered enol ether. Loss of nitrogen from the initial DielseAlder cycloadduct 25 provides the “pushepull” carbonyl ylide 26, which then undergoes a subsequent 1,3-dipolar cycloaddition with the tethered indole. Importantly, the diene and dienophile substituents complement and reinforce the [4þ2]-cycloaddition regioselectivity dictated by the linking tether. The relative stereochemistry in the cycloadduct is controlled by a combination of (1) the dienophile geometry and (2) an exclusive endo indole [3þ2]cycloaddition sterically directed to the R-face opposite the newly formed

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Scheme 7

fused lactam. This endo-diastereoselection for the 1,3-dipolar cycloaddition has been attributed to a conformational (strain) preference dictated by the dipolarophile tether (2006AGE620). Cycloadduct 27 was eventually transformed into the natural product vindoline 28 in several additional steps. Extension of these cascade studies by the Boger group eventually provided for a total synthesis of the bis-indole alkaloids vinblastine and vincristine (2009JACS4904).

3. MESOIONIC SYSTEMS Mesoionic oxazolium ylides (isom€ unchnones) correspond to the cyclic equivalent of a carbonyl ylide embedded in a heteroaromatic ring, and these reactive intermediates readily undergo 1,3-dipolar cycloaddition with suitable dipolarophiles. Isom€ unchnones are readily obtained through the transition metalecatalyzed cyclization of a suitable a-diazoimide precursor

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(1994S123). The starting diazoimides are easily constructed by acetoacylation (1985JOC1663) or malonylacylation (1982CPB1315) of the corresponding amides followed by standard diazo transfer techniques (1966CB3128). The first successful preparation and isolation of an isom€ unchnone induced by a transition metal process was described in 1974 (1974TL4475). Heating a sample of diazoimide 29 (R1 and R3 ¼ aryl, R2 ¼ methyl) in the presence of a catalytic amount of Cu2(acac)2 afforded a red crystalline material which precipitated from the reaction mixture (Scheme 8). The red solid was assigned as isom€ unchnone 30 on the basis of its spectral data and elemental analysis. Mesoionic ylide 30 was found to be air stable for several weeks, and its overall stability was attributed to its dipolar aromatic resonance structure. Formation of the isom€ unchnone ring can be rationalized by initial generation of a metallocarbenoid species which is then followed by intramolecular cyclization onto the neighboring carbonyl oxygen to form the mesoionic dipole (1982T1477). These reactive dipoles can then be trapped with a variety of dipolarophiles to give cycloadducts in high yield (Scheme 9). Interesting examples of intramolecular 1,3-dipolar cycloadditions of isom€ unchnones possessing an unactivated alkene have been reported to give rise to complex azapolycyclic compounds in one step (1989TL4077, 1994JOC1418, 1989CB1081). The 1,3-dipolar cycloaddition of isom€ unchnones derived from a-diazoimides of type 31 provides a uniquely functionalized cycloadduct (i.e., 32) containing a “masked” N-acyliminium ion (Scheme 10) (1995JOC2704). By incorporating an internal nucleophile on the tether, annulation of the original dipolar cycloadduct 32 would allow

Scheme 8

Scheme 9

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Scheme 10

the construction of a more complex nitrogen heterocyclic system, particularly B-ring homologs of the erythrinane family of alkaloids. By starting from simple acyclic diazoimides 31, the Padwa group has established a tandem cyclization cycloaddition cationic p-cyclization protocol as a method for the construction of complex nitrogen polyheterocycles of type 33. A number of approaches to complex alkaloids have been reported in which the intramolecular cycloaddition reactions of a transient isom€ unchnone dipole feature as the pivotal step for assembling the polycyclic frameworks. Thus, intramolecular reactions of isom€ unchnone dipoles generated from a series of alkenyl- and alkynyl-substituted diazoimides have been exploited to develop an approach to the quinoline ring system (rings C and D) of the ergot alkaloids (e.g., lysergic acid, 37). In one example, the Rh2(OAc)4-mediated tandem cyclization cycloaddition sequence from the diazoimide 34 led to the cycloadduct 35 in very good yield (Scheme 10) (1995JOC2704). The polycyclic adduct 35 was readily elaborated to 36 en route to ergot alkaloids via BF3$OEt2-mediated ether bridge cleavage and a Barton/McCombie deoxygenation sequence. Further attempts toward lysergic acid 37 were, however, thwarted due to the inability to isomerize the trisubstituted double bond in 36. Given the success in forming novel azabicyclic systems derived from an intramolecular isom€ unchnone cycloaddition/N-acyliminium ion cyclization

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Albert Padwa and Scott Bur

Scheme 11

sequence, this domino strategy was also used for a formal synthesis of vallesamidine 43 (1989JACS1528, 1990JOC798) via the key Heathcock intermediate 42 (Scheme 11). Thus, N-malonylacylation of the precursor amide was carried out followed by a standard diazo transfer reaction to produce the requisite a-diazoimide 38. The reaction of 38 with a Rh(II)-catalyst gave cycloadduct 39, which underwent a TMSOTf-catalyzed ring opening to furnish enamide 40 in 78% yield. With the ring-opened lactam in hand, a Barton-McCombie deoxygenation reaction (1975JCS(P1)1574) delivered 41 in 88% yield. Utilization of the sequential saponification/decarboxylation protocol afforded enamide 42 (1998JOC44). This sequence constitutes a formal synthesis of ()-vallesamidine 43, based on the successful conversion of 42 into 43 by Heathcock and Dickman (1990JOC798). Another application of the domino cascade process toward the construction of alkaloids involved the synthesis of ()-lycopodine 48 (Scheme 12) (1997JOC78). The isom€ unchnone cycloadduct 45 was formed from the Rh(II)-catalyzed reaction of diazoimide 44 and was found to be the precursor of the key Stork intermediate 47 (via 46). Formation of 47 from 46 occurred by way of a PicteteSpengler cyclization of the N-acyliminium ion derived from 45. Central to this strategy was the expectation that the bicyclic iminium ion originating from 45 would exist in a chairlike conformation (1968JACS1647, 1968PAC383, 1978JACS8036). Indeed, cyclization of the aromatic ring onto the N-acyliminium ion center

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Scheme 12

readily occurred from the axial position (1970CB615, 1971CB2937, 1979CB1329). The rearranged product 46 was then converted into the key intermediate 47 previously used by Stork for the synthesis of ()-lycopodine 48 (1968JACS1647). A further implementation of the cascade methodology involves the efficient assembly of the indolizidine ring system by using the Rh(II)-catalyzed [3þ2]-dipolar cycloaddition of the phenylsulfonyl substituted diazopyrrolidinone 49 with an appropriately substituted dipolarophile (Scheme 13). The resultant pyridone 52 represents a very versatile synthon. As depicted in Scheme 13, structural manipulation of the pyridone ring and subsequent functional group interconversions provides access to several indolizidine alkaloids (1997JOC438, 1999OL83, 1999JOC8648, 2005JOC8055). The C6 hydroxyl substituent, protected as triflate 53, allows for an assortment of cross-coupling possibilities. The Padwa group demonstrated the versatility of the method through the synthesis of the angiotensin-converting enzyme inhibitor ()-A58365A 54, ()-ipalbidine 55, b-carbolinone 56, and a variety of other novel indolizidine-based compounds (2005JOC8055). An efficient synthesis of the naturally occurring oxoindolizino quinoline mappicine ketone 62 has been carried out by Greene and coworkers (2003AGE5059) by making use of pyridone 57a as a key intermediate. The synthesis of 62 began with formation of the known cycloadduct 57a

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Scheme 13

(R1 ¼ H; R2 ¼ CO2Me) by cycloaddition of the isom€ unchnone dipole derived from diazo sulfone 57 with methyl acrylate (Scheme 14) (1997JOC438). This multistep sequence proceeded smoothly and in high yield when catalyzed by rhodium(II) acetate. Hot aqueous hydrobromic acid then effected decarbomethoxylation of 57a to give 57b in 82% yield. Etherification of 57b with commercially available (E)-1-bromo-2-pentene and cesium carbonate in dimethylformamide produced the expected substitution product 57c, which cleanly underwent a Claisen rearrangement in refluxing chlorobenzene to afford the desired rearranged derivative 58 in 74% overall yield. This transformation is a rare example of a Claisen rearrangement taking place in a hydroxypyridone system (2005JOC8055, 1983JHC471, 1995JCR386). The a-hydroxypyridone 58 was then converted into its triflate derivative under standard conditions. This was followed by Stille coupling with tetramethyltin to provide a-methyl pyridone 59 in 84% yield. In the presence of rhodium(III) chloride in hot ethanol, compound 59 was rapidly isomerized to olefin 60a (91%). The success of this key transformation derives from the carbon symmetry of the b-substituent in pyridone 59. Oxidation of 60a in two steps then

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Scheme 14

selectively generated the Friedl€ander substrate 60b, which was reacted with o-aminobenzaldehyde to give oxoindolizino quinoline 61 in 73% yield. Ozonolysis of 61 in CH2Cl2/MeOH at 78  C accomplished selective double-bond cleavage in 61 to provide mappicine ketone 62. A related synthesis of racemic camptothecin 63 was also carried out by Greene and coworkers soon thereafter and is similarly based on the isom€ unchnone dipole strategy (2005OL2989). The starting point commenced from the readily available hydroxyl-pyridone 57b (Scheme 15). Subsequent steps include a Claisen rearrangement of a functionalized allylic ether, a hindered Heck coupling, and a Friedl€ander condensation. Recently, 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. N-Diazoacetyl lactams that possess five-, six-, and seven-membered rings were transformed to the corresponding epoxy-bridged indolizidines, quinolizidines, and 1-azabicyclo[5.4.0]undecanes (66) with good to high enantioselectivities according to this method.

Scheme 15

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Scheme 16

A regio- and stereoselective ring opening of the epoxy-bridged indolizidine cycloadduct 66 gave the corresponding alcohol 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 (þ)-tashiromine (68) (Scheme 16) (2013JOC10840). Formation and dipolar trapping of the related thioisom€ unchnone dipole formed by interaction of rhodium carbenoids derived from diazo thioamides (1991CR263, 1996CR223, 1994AGE1881) have not been studied in as much detail as the isom€ unchnone system (1991SL287). Nevertheless, treatment of diazo thioamide 69 with a Rh(II) catalyst afforded cycloadduct 70 in 85% yield whose formation is derived from the intramolecular [3þ2]-cycloaddition of a mesoionic dipole intermediate (2005OL2925). An alternative method that has also been used to generate thioisom€ unchnones involves treatment of thioamides with bromoacetyl chloride in the presence of triethylamine (1994S993). In the case of the cis-aryl alkenyl-substituted piperidinethione 71, this reaction resulted in the formation of cycloadduct 73 in 85% yield as a single diastereomer (Scheme 17) (2005OL2925). The unusual structure of the schizozygane alkaloid family has made them challenging targets for total synthesis (2005TL7909, 1999OL1315). On the basis of the cycloaddition results using the thioisom€ unchnone system as outlined in Scheme 17, the Padwa laboratory carried out an approach toward a synthesis of the isoschizozygane alkaloid ()-isoschizogamine (77) (2005OL2925). The hexacyclic skeleton of the isoschizozygane alkaloid skeleton could be prepared from a compound of type 76 by a sequence of

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Scheme 17

enamide protonation, N-acyliminium ion cyclization, and lactamization. Enamide 76 would be generated by extrusion of sulfur from cycloadduct 75 followed by reduction of both the nitro and keto groups and a subsequent dehydration. The key cycloadduct 75 was accessible from an intramolecular dipolar cycloaddition of the thioisom€ unchnone dipole 74 (Scheme 18). Further studies are required before this alkaloid synthesis can be fully realized.

Scheme 18

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Scheme 19

The well-known pharmaceutical drug Atorvastatin, marketed under the trade name Lipitor, is a member of the drug class known as statins, which are used primarily for lowering blood cholesterol and for prevention of events associated with cardiovascular disease. Since Atorvastatin (80) is one of the top selling pharmaceuticals, it has been the subject of many synthetic studies aimed to improve its preparation, particularly the pyrrole core and pendant chiral diol. In a recent report, Gribble and Lopchik (2015TL3208) described the preparation of 80 in seven steps from commercially 4-fluorophenylacetic acid. The key step involved a 1,3-dipolar cycloaddition of the complex m€ unchnone mesoionic heterocycle 79 with N,3-diphenylpropiolamide as shown in Scheme 19 (1964AGE136, 2014AGE9708).

4. AZIDES Azides are very versatile and valuable synthetic intermediates, known for their wide variety of applications, and have been employed for the synthesis of a number of important heterocyclic compounds. Azides also represent a prominent class of 1,3-dipoles, and their cycloaddition to multiple pbonds is an old and widely used reaction (1988CR297). The dipolar cycloaddition of an azide to an alkene furnishes a triazoline derivative (2003MI623). Azide-alkene cycloadducts can extrude nitrogen at elevated temperatures to form aziridines or imines, depending upon the substrate and reaction conditions. The cycloaddition of azides with alkynes affords triazolidine derivatives which have been a focus in the area of chemical biology and have received much recent attention (2008AGE2596, 2008CR2952). In this section of our review, we recount some developments of the 1,3-dipolar cycloaddition reaction of azides that have been used for the synthesis of various alkaloids.

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Scheme 20

Due to its strong cytotoxicity and intriguing molecular structure, the marine alkaloid communesin F (84) attracted the attention of the Weinreb group (2010JOC2000). A critical step in his overall synthesis of this alkaloid involved an interesting bimolecular dipolar cycloaddition using cyanogen azide. Thus, base-induced deprotection of enamide 81 followed by treatment with in situ generated cyanogen azide (1964JACS4506) afforded N-cyanoamidine 3 (Scheme 20). This transformation occurs through an initial [3þ2]-dipolar cycloaddition of the enamine with the transient azide to first produce the triazoline cycloadduct 82, which rearranges spontaneously to afford 83. Basic hydrolysis of amidine 83 gave the corresponding lactam, and a subsequent acylation led to an acylated lactam which was eventually transformed into the marine fungal alkaloid ()-communesin F (84). The intramolecular dipolar cycloaddition of alkyl azides with enones has been frequently utilized for alkaloid synthesis, and this strategy has been employed since the early 1980s with important contributions being made by Schultz (1980JOC5008, 1984JOC1676, 1988MI153), Sha (1984CC492, 1984H566, 1986JOC1490), Molander (1997TL4347, 2002TL5385), and Pearson (1990TL5441, 1990TL7571) among others. Much of the earlier research was focused on mechanistic issues related to the breakdown of the presumed triazoline intermediates. More recently, a new one-pot procedure

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Scheme 21

for the preparation of amino-enones from chloralkyl enones and sodium azide was reported by Tu and coworkers (2010JOC5289). Azido-enone 85 underwent an intramolecular dipolar cycloaddition reaction to produce a triazoline intermediate of type 86. This transient species further rearranged to produce a-aminoenone 89 via intermediates 87 and 88 (Scheme 21). In a further demonstration of this strategy, a convergent synthesis of the alkaloid hexahydroapoerysopine (94) was also achieved by Tu and coworkers (2010JOC5289). As shown in Scheme 22, treatment of enone 90 with sodium azide in DMF at 60  C afforded a-aminoenone 92 in 47%

Scheme 22

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Scheme 23

yield. The structure of a presumed triazoline intermediate related to 91 was confirmed by X-ray analysis. The overall tandem cycloaddition/rearrangement sequence of 90 afforded the key compound 92 that was ultimately employed for an eventual synthesis of 94 by the route shown in Scheme 22. In a related example, Sha and coworkers reported on the intramolecular cycloaddition of azido-enone 95 as the key step for a total synthesis of ()-desamylperhydrohistrionicotoxin 98 (Scheme 23) (1991JOC2694). The reaction sequence proceeds by an initial dipolar cycloaddition of azide 95 to produce the unstable triazoline 96 which undergoes a subsequent loss of nitrogen to give aziridine 97 that was ultimately converted to 98. An expedient synthesis of several naturally occurring phenanthro-indolizidine alkaloids was reported by Kim and coworkers (2007JOC4886) making use of an intramolecular 1,3-dipolar cycloaddition of an azide onto an alkene and subsequent reduction of the resulting imine and aziridine. Heating azidoalkene 99 at 135  C produced a 3:1-mixture of 100 and aziridine 101. Catalytic hydrogenation of the mixture followed by a Pictete Spengler cyclomethylenation of the resulting reduced product transformed the cyclized compounds 100 and 101 into the phenanthroquinolizidine alkaloid Cryptopleurine 102 (Scheme 24). The authors were also able to accomplish the synthesis of the related phenanthroindolizidine Antofine 103 by a similar reaction sequence. A related sequence was used by Kozikowski and Greco for a total synthesis of ()-clavicipitic acid (107) (1984JOC2310). On heating azide 104 at 190  C, the initially formed triazoline intermediate 105 underwent loss

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Scheme 24

Scheme 25

of nitrogen to give imine 106. This key structure was smoothly transformed to the target alkaloid 107 in three subsequent steps (Scheme 25). Pearson and Lin developed an elegant approach to the synthesis of optically active ()-swainsonine (114) starting from azide 108 (1990TL7571). Heating 108 at 80  C in benzene followed by base treatment and an ensuing hydroboration/oxidation gave indolizidine 113 in 70% overall yield. The thermolysis reaction of 108 proceeds by a 1,3-dipolar cycloaddition across the tethered p-bond, and this was followed by nitrogen extrusion to produce imine 110. Displacement of the chloro group by the imine nitrogen atom gave iminium ion 111 which subsequently lost a proton to afford 112 and eventually 113 via hydroboration/oxidation. Cleavage of the

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Scheme 26

acetonide unit in 113 using 6N HCl produced the target molecule 114 in 85% yield (Scheme 26). Further utilization of this general method for the preparation of other alkaloids was subsequently demonstrated by Pearson and Schkeryantz in the total synthesis of ()-lycorane (118) (1992JOC6783). The intramolecular 1,3-dipolar cycloaddition of azide 115 in benzene at 140  C followed by extrusion of nitrogen gave the unstable iminium salt 117. This intermediate was then reduced with sodium borohydride to afford ()-g-lycorane 118 in 63% yield from azide 115 (Scheme 27). Mann and coworkers recently demonstrated the synthesis of the pyrrolizidine alkaloid amphorogynine C 122 using an azido-olefin dipolar cycloaddition as the key step (2012EJO4347). Heating a sample of azide 119 in toluene at 140  C for 24 h produced triazoline 120 which subsequently lost nitrogen to give imine 121 along with lesser quantities of an aziridine by-product. Imine 121 was eventually converted into the natural product 122 in several additional steps (Scheme 28).

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Scheme 27

Scheme 28

Recently, a high yielding synthesis of a,b-unsaturated alkylimines was developed using azides tethered to an allylic alcohol (i.e., 123) (2012OL5728). Thus, treatment of 123 with p-toluenesulfonic acid gave rise to unsaturated imines of type 125. A very reasonable pathway to explain this result would involve an initial 1,3-dipolar cycloaddition to give triazoline 124 as a transient intermediate which is easily dehydrated to produce the observed product (Scheme 29). The efficiency of the method was nicely demonstrated by the total synthesis of the Costa Rica ant venom alkaloid 127 from the MOM-masked cyclization precursor 126.

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Scheme 29

The pentacyclic alkaloid ()-meloscine (134) was prepared by Feldman and Antoline using a clever allenyl azide cycloaddition/cyclization cascade to deliver the core azabicyclo[3.3.0]octadiene substructure (2012OL934). Strain-driven release of nitrogen from the dipolar cycloadduct 129 derived from 128 promotes formation of the azatrimethyl-enemethane diradical 130 en route to the bicyclic product 131 (Scheme 30). For the synthesis of meloscine 134, the thermolysis of a dilute solution of allene 132 in toluene gave the desired bicycle 133 whose structure was established by single crystal X-ray analysis. Subsequent manipulation of the peripheral functionality in 133 then delivered ()-meloscine 134.

5. AZOMETHINE YLIDES Several methods have been used to generate azomethine ylides for use in dipolar cycloaddition chemistry (1984MI1). A particularly common method is the condensation of N-alkyl amino acid derivatives with aldehydes followed by decarboxylation to afford the 1,3-dipole. The Coldham group employed this method in their strategy for the synthesis of a variety of alkaloids. In a formal synthesis of deethylibophylidine, for example, heating a toluene solution of aldehyde 135 and N-allyl glycine (136) at reflux produced 137 in 42% yield (Scheme 31) (2007EJO2676). The N-allyl group was subsequently removed to furnish 138 in 40% yield, which represents an intermediate in the synthesis of deethylibophyllidine (139).

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Scheme 30

Scheme 31

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Scheme 32

Lovely et al. used a [3þ2]-cycloaddition reaction as the key step in an approach to martinellic acid 147 (2007TL2607). In this synthesis, the reaction of aldehyde 140 with benzyl glycine 141 produced 16% of 142 and 51% of tricyclic 143, as well as the trans-diastereomer in 7% yield (Scheme 32). Elaboration of the piperidine ring, installation of a carbomethoxy group on the aromatic ring, and removal of protecting groups furnished 144. Finally, a AgNO3-mediated guanylation of 144 with 145 gave 146 in 62% yield. This constitutes a formal synthesis of martinellic acid 147, as the hydrolysis of the ester was previously reported. The condensation of secondary N-(trimethylsilyl)methyl amines with carbonyl compounds has been shown to generate unstabilized azomethine ylides upon desilylation. For example, the ACD azatricylic 152, which represents the core of the calyciphylline A-type daphniphyllum alkaloid 153, was formed in 55% yield by mixing 148 and 149 in DMF at rt in the presence of catalytic amounts of H3PO4 (Scheme 33) (2015TL2492). In this cascade sequence, condensation of the amine with aldehyde 148 produced iminium ion 150. Cleavage of the silyl group then gave azomethine ylide 151 that underwent cycloaddition across the pendant electron-deficient alkene to produce 152. Stabilized azomethine ylides can easily be formed using amino acids and their esters to generate an imine that is subsequently alkylated to generate an iminium ion. Decarboxylation or deprotonation then affords the reactive azomethine ylide. Coldham and coworkers examined the scope of this type of “condensationealkylationecycloaddition” cascade wherein the

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Scheme 33

acid-catalyzed condensation of 154a with glycine ethyl ester 155 followed by intramolecular cyclization generated azomethine ylide 156a. This 1,3dipole then cycloadded across the pendant olefin to give 157a in 81% yield as a single diastereomer (Scheme 34) (2009JOC2290). Likewise, 154b,c produced 157b,c in 72% and 51% yield, respectively. Alternatively, 154d underwent the cascade sequence to produce 158 in 74% yield. Presumably, the increased conformational flexibility in this system allows a transition state that gives rise to the trans-fused product. Application of this cascade to the synthesis of natural products began with the exposure of 159 to glycine,

Scheme 34

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Scheme 35

giving amine 160 in 79% yield. Hydrolysis of the ketal group delivered ketone 161 in 89% yield, which was subsequently converted into aspidospermidine 162 and several other aspidospermine alkaloids through Fischer indole syntheses. There are also several examples of imidate-derived azomethine ylides reported in the literature. For example, the Gin group described a clever use of these 1,3-dipoles in an approach to the azatricyclic core of some stemofoline members of the stemona alkaloid family. The formation of the azomethine ylide 164 occurred upon exposure of pyrrolidine 163 to triflic anhydride and tetrabutylammonium triphenyldifluorosilicate (TBAT; Scheme 35) (2008T3629). Cycloaddition of the resulting dipole across the pendant vinyl sulfide furnished 165 in 71% yield. Enol triflate 165 was then reduced to give the saturated side chain in 166 in 89% yield by the action of Pd/C under an H2 atmosphere. The enolate derived from 166 was treated with ethyl iodoacetate in the presence of hexamethylphosphoramide (HMPA) followed by

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Scheme 36

epimerization of the alkylation product to provide 167 in 58% yield from 166. Concomitant hydrolysis of the methyl ester and the acetonide protecting group gave 168 in 96% yield, an intermediate that contained suitable functional handles that could be elaborated into stemofoline 169. In an approach to the compact, polycyclic core of some daphnane alkaloids, the Bélanger group employed a sequential “VilsmeiereHaackeazomethine ylide cycloaddition” sequence (Scheme 36) (2011OL6204). Formamide 170 was reacted with Tf2O and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) at rt to produce an iminium ion which underwent reaction with the silyl enol ether moiety followed by loss of triflate to produce iminium ion 171. Addition of iPr2EtN to the reaction mixture then generated azomethine ylide dipole 172 that reacted with the a,b-unsaturated ester to give tetracyclic 173, a species common to both the daphnilactone B-type alkaloids 174 and yuzurimine-type alkaloids 175. Pandey and coworkers developed an AgF-mediated route to azomethine ylides starting from N,N0 -bis(trimethylsilylmethyl)alkyl amines and applied this method of dipole formation toward a formal total synthesis of the Amaryllidaceae class of alkaloids. Exposure of 176 to AgF effected a double desilylation and oxidation to furnish a transient azomethine ylide dipole (Scheme 37) (2011EJO4571). Cycloaddition of the dipole to the proximal enone fashioned tetracycle 177 in 56% yield. A base-mediated hydrolysis of the benzoyl ester occurred with concomitant epimerization, giving 178

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Scheme 37

in 98% yield. Conversion of the hydroxyl group in 178 to a mesylate followed by reaction with potassium bis(trimethylsilyl)amide (KHMDS) produced 180 in 65% yield via enolate 179. The alkene moiety in compound 182 was installed in 71% yield by a reductive elimination of an enol triflate derived from 181 using Pd(PPh3)4 and Et3SiH. The Overman group had previously synthesized pancracine 185 from compound 182, thereby resulting in a formal synthesis of this alkaloid. With the general cycloaddition strategy established, a next generation synthesis employed a chiral auxiliary to control the overall diasteroselectivity. Thus, exposure of 183 to AgF followed by reduction with LiAlH4 afforded 184 in 46% yield and with 63% enantiomeric excess after recrystallization. Tetracycle 184 was then used to complete an asymmetric formal synthesis of 185 and several related alkaloids. In an approach to the stemofoline class of alkaloids, the Martin group discovered an unusual set of conditions for generating azomethine ylides. Oxidation of compound 186 under Swern conditions afforded a 5:1 mixture of 189 and 190 in 69% yield (Scheme 38) (2011TL2048). The formation of these two molecules can be easily rationalized via an intramolecular 1,3dipolar cycloaddition of dipole 188, but the mechanism through which the azomethine ylide is formed under Swern conditions is not well understood. The authors proposed that the oxidized product 187a derived from 186 reacted with one of the electrophilic species formed under the reaction

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Scheme 38

conditions to give 187b. A subsequent loss of a proton as well as the leaving X group would then produce dipole 188. Even with considerable experimentation, the inability to easily remove the cyano group in structures 189 and 190 necessitated an alternate route to the key azomethine ylide intermediate. Ultimately, Martin and coworkers settled on the intramolecular reaction of the imino group in compound 191 with the critical carbenoid intermediate being obtained by a rhodium(II)-catalyzed decomposition of the diazo group in 191 so as to provide dipole 192 (Scheme 39) (2013T7592). Subsequent cycloaddition of the resulting azomethine ylide with the tethered alkene afforded 193 in 75% yield. Tricycle 193 was

Scheme 39

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subsequently transformed into (þ)-194, an intermediate used by Overman in a synthesis of ()-didehydrostemofoline and isodidehydrostemofoline.

6. AZOMETHINE IMINES Although a few examples of dipole methodology directed toward various classes of natural products have been reported using azomethine imine cycloadditions, there are far fewer natural products synthesized using these reaction partners than azomethine ylides. The Overman group deployed this type of dipolar cycloaddition in the syntheses of (þ)-Nanakakurines A and B (195a,b), respectively (Scheme 40). One of the most challenging problems encountered in this synthesis was fashioning the piperidine spirocycle such that the nitrogen on C(5) was on the concave face of the decahydro-3,5-ethanoquinoline system. This was accomplished through an intramolecular

Scheme 40

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cycloaddition of the azomethine imine dipole derived from hydrazide 196. Reacting a toluene solution of 196 with excess paraformaldehyde in the presence of both 4  A mol sieves and iPr2NEt at 120  C produced 197 in 85% yield (2010JOC7519). The use of a base additive was crucial for the reaction to proceed. Under the acidic conditions, the required dipole 199 was slow to form. Instead, the initially formed iminium ion intermediate 198 undergoes an aza-Prins cyclization to furnish compound 201 via cation 200, rather than give the dipolar cycloadduct 197. Subsequent functional group manipulation of 197 so as to cleave the NeN bond and close the piperidine ring gave 195a, which was then converted into 195b. A number of natural products contain C(1)-substituted tetrahydroisoquinolines as their core unit (e.g., coclaurine, 202, Scheme 41) (2014CEJ6592). Wang and coworkers developed an organocatalyzed approach toward 202, wherein azomethine imine 203a was mixed with aldehyde 204a, AcOH, and catalyst 205 in anisole at 40  C to give an unstable cycloadduct that

Scheme 41

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Scheme 42

was immediately reduced with NaBH4 to afford 206a in 88% yield, with greater than 25:2 diastereoselectivity, and 99% enantiomeric excess. Variously substituted azomethine imines reacted well under similar conditions. For example, 203b afforded 206b in 85% yield, and 203c produced 206c in 84% yield; both substrates reacted with the same selectivities as 203a. Longer-chain aldehydes also worked well in the reaction, with 203a and 204b reacting in the presence of the catalyst to give 206d in 85% yield and with no loss in selectivity. The reaction probably occurs through condensation of the organocatalyst with the aldehyde to give an enamine 207. An inverse electronedemand cycloaddition with 203 produces N,N-acetal 208 that decomposes under acidic conditions to provide iminium ion 209. Hydrolysis of 209 would then give aldehyde 210, which is reduced by NaBH4 to give the isolated products. This methodology was expanded to the reaction of a,b-unsaturated aldehydes with azomethine imines 203 which resulted in cycloaddition across the double bond of the intermediate dienamines. For example, the reaction of 203a with 211a was mediated by the prolinol derivative 212 (20 mol%), and the intermediate product was immediately exposed to NaBH4, giving 213a in 87% yield and with 97% enantioselectivity (Scheme 42) (2014CER6592). Reactions with aldehyde 211 were found to occur best when 2,4-dinitrobenzoic acid was used as an additive. Under these conditions, 203b and 203c reacted with 211a to give 213b and 213c in 88% yield (99% ee) and 92% yield (92% ee), respectively. In all three cases, the diastereoselectivity was >25:1. Addition across the 4,5-alkenyl p-bond

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only occurred when the dienamine was conjugated into an aromatic ring. When 211b was exposed to 203a in the presence of the prolinol catalyst and acid, a normal electron-demand cycloaddition across the a,b-unsaturation of the intermediate iminium ion occurred, and NaBH4 reduction of the crude mixture produced 214 in 82% yield and with 80% enantiomeric excess. The cycloaddition of 203 with the trienamine derived from 215 and 212 afforded, after exposure to NaBH4, a 4:3 mixture predominating in 216 in 80% yield and with 92% ee. The other diastereomer was isolated with 72% enantiomeric excess. There are a variety of 1H-pyrrolo-[1,2-a]indole-based natural products reported in the literature, such as mitomycine C (217) and isatisine A (218) (2014TL3064). Sharada and coworkers developed a microwave-assisted cycloaddition approach to these kinds of scaffolds. Thus, microwave irradiation of an ethanol solution containing aldehyde 219a, phenylhydrazine and HCl for 1 h at 80  C produced 220a in 52% isolated yield (Scheme 43).

Scheme 43

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The mechanism involves condensation of the hydrazine with the aldehyde to generate the intermediate azomethine imine 221, which cycloadds across the pendant alkene to give 222. Spontaneous oxidation of 222 then produced 220. As demonstrated by the reactions of 219bed, a variety of substituents on the aryl ring were tolerated, giving rise to compounds 220bed in 51%, 37%, and 43% yields, respectively. While the nitroaryl systems returned complex reaction mixtures, the heterocylic system 219e gave 220e in 50% yield.

7. NITRONES 1,3-Dipolar cycloaddition of nitrones (1984MI1) continues to play an important role in alkaloid synthesis. For example, Dhavale and coworkers used carbohydrate-derived nitrones for the synthesis of polyhydroxylated indolizidines and perhydro-azaazulene alkaloids. Thus, the D-glucosederived nitrone 223 was reacted with allyl alcohol in refluxing acetone for 48 min, and this was followed by exposure of the resulting mixture of cycloadducts to p-TsCl and pyridine which afforded a mixture of 224aed in 87% combined yield in a 56:8:20:16 ratio (Scheme 44) (2005JOC1356). Transfer hydrogenation conditions resulted in the removal of both the benzyl-protecting groups and also cleaved the NeO bond in 224a,b. The resulting amino group displaced the tosylate functionality and reprotection of the nitrogen atom produced 225a,b in 74% and 70% yield, respectively. Deprotection of the acetonide group was accomplished with aqueous TFA, and subsequent hydrogenation conditions both removed the nitrogen protecting group and effected a reductive amination to afford 226a,b in 80% and 86% yields, respectively. Stereoisomers 224c,d were subjected to similar conditions and provided 226c,d. Using the same methodology, the D-galactose-derived nitrone 227 gave 228a,b (2007TA1176). The Chmielewski group has published extensive studies on the addition of cyclic nitrones to a,b-unsaturated d- and g-lactones. While fivemembered ring nitrones (e.g., 229) react with d-lactones (e.g., 230) exclusively via an exo-approach because of unfavorable steric interactions, they react with g-lactones (231) through both endo- and exo-transition states, giving rise to mixtures (Scheme 45) (2006TA68). Lactones bearing substituent groups react in such a way that the nitrone approaches the p-bond from the face of the alkene opposite the substituent. Cyclic nitrones can adopt conformations that clearly define the location of a substituent on the dipole. For example, reaction 232 with 231 produced only two

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Scheme 44

stereoisomers, 233 and 234 in a ratio of 84:16. In this case, both isomers arise from addition anti-to the t-butoxy group. However, 234 comes from an endo-transition state while 233 must go through an exo-transition state. The reaction of lactone 231 with nitrone 235 produced three products 236, 237, and 238 in a 35:53:12 ratio. In this case, cycloadduct 236 comes about from an exo-approach of the lactone to the nitrone that is anti to the t-butoxy group. On the other hand, cycloadduct 237 arises from an exoapproach that is syn to the t-butoxy group while 238, which is produced by an endo-approach, occurs anti to the t-butoxy group. With both substituted nitrones and substituted lactones, double asymmetric induction can increase the stereoselectivity of the cycloaddition. For example, the cycloaddition of nitrone 239 with lactone 240, which represents a matched set, provides only cycloadduct 241 in 81% yield (Scheme 46) (2006TA68). Alternatively, the reaction of mismatched set 243 and 240 produced a mixture (45:32:23) of 244, 245, and 246 in 77%

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Scheme 45

Scheme 46

combined yield. Cycloadduct 241 can easily be transformed into pyrrolizidine 242, a potential D-glucosidase inhibitor in 26% overall yield (2008CR2215), as well as other pyrrolizidines (2009CR167). The glucosidase and glycosyltransferase activities of naturally occurring polyhydxoxylated indolizidines and pyrrolizidines (e.g., castanospermine

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Scheme 47

and casuarine) have made these azasugars attractive platforms for the application of nitrone chemistry (2009T2322, 2011SL1668). For example, the Darabinose-derived nitrone 247 reacted with enantiomerically enriched allylic alcohol 248 to afford isoxazolidine 249 in 70% yield (Scheme 47) (2009JOC5679). The hydroxyl group in 249 was then converted into the mesylate ester 250 in 74% yield. The action of Zn in AcOH cleaved the NeO bond, and cyclization of the resultant amine occurred under the reductive conditions by displacement of the mesylate group, giving 251 in 60% yield. Removal of the acetate functionality using Ambersep 900 resin was followed by global deprotection of the benzyl ethers under palladium-catalyzed hydrogenation conditions to furnish 252 in 71% yield from 251. Chattopadhyay’s group has presented an interesting strategy to access quinolizidine scaffolds using an intramolecular 1,3-dipolar cycloaddition reaction of nitrones. The key step in the synthesis of ()-lasubine II (261) corresponded to the thermolysis of nitrone 253 which afforded cycloadduct 254 in 81% yield (Scheme 48) (2011OL5128). Deprotection of the acetal functionality produced diol 255 that was oxidatively cleaved by the action of NaIO4. Reaction of the intermediate aldehyde with the phosphorous ylide derived from 256 provided azaoxa-bicycle 257 in 86% yield from 255. Selective hydrogenation reduced the carbonecarbon double bond, and a subsequent exposure to Zn in AcOH opened the bicycle to give piperidine 258 in 83% yield. Protection of the alcohol in 255 as a TBS ether was followed by hydrogenolysis of the benzyl ether to furnish 259 in 76% yield.

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Scheme 48

Construction of the quinolizidine skeleton was then accomplished via a Mitsunobu reaction, providing 260 in 75% yield. Exposure of 260 to the action of Et3N$HF removed the TBS-protecting group, and the resulting secondary alcohol was inverted under Mitsunobu conditions to give ()-lasubine II 261 in 58% yield from 260. A similar strategy was used to produce both the alkaloid (þ)-241D (262) and its enantiomer (2012JOC11056). Borschberg and H€ ock reported the synthesis of the iboga alkaloid 268 using a “condensation/cycloaddition cascade” to fashion the 8-azabicyclo [2.2.2]octane substructure. The synthesis starts with an IrelandeClaisen rearrangement of allyl ester 263 followed by a subsequent manipulation of the carboxyl group which furnished an inseparable mixture (96:4) of 264 and its C(4) epimer in 65% combined yield (Scheme 49) (2004TA1801). Exposure of acetal 264 to aqueous H2SO4 (1.5 M) for 8 h at 47  C first gave rise to nitrone 265 that then added across the proximal alkene to provide a mixture (96:4) of 266 and 267 in 67% yield. Azabicycle 266 was subsequently transformed into the alkaloid 268 over nine steps in 20% yield (2006HCA542). The Murray lab has reported a synthesis of “alkaloid-like” pyrroles when nitrone 269 was heated with several alkynes (2007JOC3097). Thus, the thermolysis of a mixture of nitrone 269 and alkyne 270a at reflux in toluene

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Scheme 49

for 2 h furnished 271a in 59% yield (Scheme 50). Under similar conditions, alkyne 270b,c produced 271b,c in 56% and 43% yield, respectively. When phenyl alkyne 270d was used, the mixture required heating for 15 h to afford 271d in 43% yield. The proposed mechanism starts with a 1,3-dipolar cycloaddition of the nitrone across the triple bond to give 272, which could actually be isolated if the reaction was run at lower temperatures. A subsequent rupture of the NeO bond leads to aziridine 273 after bond reorganization. Cycloreversion of the transient aziridine gives azomethine ylide 274 which readily tautomerizes to enamine 275. Finally, addition of the enamine moiety to the proximal ketone generates iminium 276 which eliminates a molecule of water to furnish the substituted pyrrole 277. Goti and coworkers have explored the intramolecular 1,3-dipolar cycloaddition of cyclic nitrones as an approach toward the construction of polyhydroxylated tropanes. In this plan of attack, the reaction of the D-arabinose-derived nitrone 278 with excess allylmagnesium bromide gave hydroxylamine 279 in 88% yield and with greater than 98% diastereoselectivity (Scheme 51) (2011JOC4139). Oxidation of 279 using MnO2 produced nitrone 280 in 73% yield, together with several other isomers.

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Scheme 50

Scheme 51

The thermolysis of 280 in a sealed tube afforded 281 in 97% yield. Finally, exposure of 281 to hydrogen gas in the presence of catalytic amounts of Pearlman’s catalyst and acidic methanol cleaved the NeO bond and also deprotected the hydroxyl groups to furnish nortropane 282 in quantitative yield.

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Scheme 52

A microwave-promoted cycloaddition of nitrone 283 across the p-bond of alkene 284 started Caprio’s synthesis to the core structure of halichlorine (291). This reaction afforded isoxazolidine 285 as a 1:1 mixture of diastereomers in 78% yield (Scheme 52) (2011OBC2981). Selective protection of the diol followed by oxidative cleavage of the NeO bond by the action of mCPBA produced 286 in 86% yield for the two steps. Reaction of 286 with NaBH4 selectively reduced the nitrone, and the resultant hydroxylamine was further reduced to 287 by the action of Zn in the presence of NH4Cl in aqueous ethanol and catalytic amounts of indium in 89% yield. Diol 287 and MsCl/Et3N were mixed using CH2Cl2 as the solvent at 0  C, and then the mixture was heated to reflux which provided 288 in 99% yield. The benzyl ether present in 288 was treated with LiDBB, and a DesseMartin periodinane reaction oxidized the newly deprotected alcohol with concomitant elimination of the mesylate group to afford the

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283

Scheme 53

unsaturated aldehyde 289 in 71% yield. Further oxidation and esterification followed by cleavage of the silyl ether furnished 290 in 45% yield from 289 and which contains functional handles for installing the macrolide ring of 291. Using this 1,3-dipolar cycloaddition strategy, Caprio also fashioned compound 292, which is the core structure present in pinnaic acid 293. Recently, the Martin group used a previously employed route to the yohimbine and corynanthe alkaloids (1988JACS5925) to generate a 180member library for screening at both the NIH Molecular Library Probe Production Center and the National Institute of Mental Health’s Psychoactive Drug Screening Program. In their general synthesis, toluene solutions of crotyl amides 294aec were heated with N-methyl hydroxylamine hydrochloride in the presence of Et3N to give 295aec in 60%, 43%, and 38% yields, respectively (Scheme 53) (2013ACS379). Exposure of 295a to LiAlH4 furnished 296 in 98% yield. The Pd-catalyzed cross-coupling of 295b,c with boronic acids was a major point for increasing diversity in this library. For example, when 295c was heated in toluene with phenyl boronic acid in the presence of Pd(dppf)Cl2 and Cs2CO3, it provided 297 in 68% yield. Reductive cleavage of the NeO bond by action of NiCl2 and NaBH4 produced amine 298, and this also opened up another site for increasing the diversity of the library. In another example, the reaction of

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298 with 299 afforded 300 in 99% yield. Both compounds 296 and 300 were found to be biologically active in initial screens, though more complete screening data were not presented.

8. NITRILE OXIDES The nitrile oxide class of 1,3-dipoles are readily accessible from aldoximes or nitroalkanes by simple procedures, and they undergo smooth 1,3dipolar cycloaddition reactions with a variety of dipolarophiles (2002MI361). In particular, they form synthetically useful isoxazoles and dihydroisoxazoles with alkynes and alkenes, respectively. Especially important are cycloadditions with monosubstituted alkenes since these reactions are regioselective, normally affording dihydroisoxazoles with substituents located at the C5 position. These heterocycles are quite useful as precursors for a variety of other compounds and their functionality can be readily unmasked through simple transformations. Thus, reductive cleavage of the NeO bond of the dihydroisoxazole reveals a b-hydroxyketone and provides a convergent route to carbon backbones suitable for the formation of various spiroketals. Dihydroisoxazoles are also well-known precursors of amino alcohols and a-hydroxy-cyclopentanones (1984MI291). The regioselectivity of the [3þ2]-process with an alkenyl alcohol can be controlled by chelation of the nitrile oxide oxygen atom though the formation of a magnesium alkoxide (1994JACS2324), a method which has been for polyketide construction (2005OL2011). An interesting approach to the canthin-4-one alkaloid family has recently been reported by Tremmer and Bracher and involves a 1,3-dipolar cycloaddition of the readily available 1-ethynyl-b-carboline 301 with various nitrile oxides (Scheme 54) (2015T4640). The initially formed isoxazoles 302 were then cleaved reductively, and this was followed by heating the resulting enaminoketones 303 in DMF at 150  C to give 6-substituted canthin-4-ones 304 in high yields. A 1,3-dipolar cycloaddition using a nitrile oxide dipole was described by Roth and Singh as an approach to the 3-hydroxy-3-alkyl oxindole scaffold (2011OL2118). Spirocyclic isoxazoline 307 was obtained by cycloaddition of nitrile oxide 305 with 3-methylene oxindole 306 and was further elaborated to 3-hydroxy-3-cyanomethyl oxindole 308. This novel protocol was then used to synthesize the tricyclic pyrrolidinoindoline natural product ()-alline 310 via the tricyclic intermediate 307 (Scheme 55). Thus

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Scheme 54

Scheme 55

treatment of 3-methylene oxindole 306 with the in situ generated nitrile oxide 305 afforded the expected isoxazoline 307 as a single regioisomer. Investigation into the nature of the base indicated that the reaction provided the best results when the dipole species was generated with a basic resin (Amberlyst A21) and introduced directly into the reaction as a solution in dichloromethane. Due to the propensity of the dipole to dimerize, it was necessary to employ an excess of the nitrile oxide dipole (3 equivalent) to achieve good yields. The cycloaddition reaction was highly regioselective (>20:1), and the resulting structure was unambiguously proven through single crystal X-ray diffraction of a derivative obtained via hydrogenolysis.

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Scheme 56

Chemoselective benzyl protection of the cyanoalcohol 308 afforded the N-benzyl derivative in 92% yield. LiAlH4-promoted reductive cyclization cleanly gave the fused tricyclic intermediate 309 in excellent yield. Subsequent reductive monomethylation using HCHO/NaCNBH3 furnished the expected alcohol which underwent debenzylation with sodium naphthalenide to give ()-alline 310. The alkaloid clausenamide contains a densely substituted pyrrolidinone ring with four contiguous stereocenters and has shown potent nootropic activities in many behavioral experiments. A facile regio- and diastereoselective nitrile oxide cycloaddition method using magnesium-coordinated chelation control of a chiral a-alkoxymethyl ether nitrile was employed as the key step in a formal synthesis of ()-clausenamide (14). Tanda and Yamasaki have developed a synthetic route toward the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines by using of a combination of alkoxymethyl ether nitrile oxides derived from hydroximoyl chloride 311 with magnesium alkoxide (1994JACS2324, 2001AGE2082). This facile approach toward the synthesis of substituted 2-isoxazolines was subsequently applied to a formal total synthesis of 314 (2014SL2953). The outline of their synthetic strategy toward the clausenamides is illustrated in Scheme 56. The clausenamides were synthesized from 2-isoxazoline 313 by (1) oxidation and esterification, (2) selective reduction, and (3) NeO bond cleavage and subsequent recyclization to construct the pyrrolidinone ring. 2-Isoxazoline 313 was obtained by a putative 1,3-dipolar cycloaddition of nitrile oxide 312 with cinnamyl alcohol from the less hindered face in an exo-fashion.

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Scheme 57

The ability of an isoxazoline to serve as a masked g-amino alcohol for alkaloid synthesis has been used by many research groups over the years. For example, a total synthesis of the ergot alkaloid (þ)-paliclavine 318 in optically active form was reported by the Kozikowski group and is based on an intramolecular nitrile oxide cycloaddition reaction (INOC) with a neighboring olefinic appendage bearing an allylic asymmetric center (1984T2345). On subjecting the 3,4-disubstituted indole 315 to phenyl isocyanate/triethylamine, the desired nitrile oxide intramolecular cycloaddition reaction occurred in high yield to afford isoxazolines 316a,b as a 1:1 mixture of diastereomers which were subsequently converted to alkenes 317a,b. The inseparable mixture of isomers was then reacted with aluminum amalgam in wet THF to yield a mixture of (þ)-paliclavine 318 and epi-paliclavine (Scheme 57). The INOC reaction also plays a crucial role in the synthesis of the transhydrindane derivative 322, a potential intermediate for the synthesis of the C2-symmetric pentacyclic alkaloid papuamine 319 (1997CC495). Nitroalkene 321 was prepared from racemic anhydride 320 in a few steps. Nitrile oxide formation was then carried out in situ by the reaction of 321 with PhNCO which resulted in cyclization to afford the racemic trans-hydrindane 322 (Scheme 58). A stereocontrolled total synthesis of (þ)-vinblastine (329), a prominent alkaloid used in cancer chemotherapy, was reported by the Fukuyama/ Tokuyama team and features an INOC reaction for the preparation of a key reaction intermediate utilized in their synthesis (2010CR101). Thus, the oxidation of oxime 323 with sodium hypochlorite generated the expected nitrile oxide 324 which underwent a subsequent 1,3-dipolar cycloaddition to produce isoxazoline 325 as a single isomer (Scheme 59). The INOC proceeded via a six-membered chairlike transition state (i.e., 324) to furnish 325 with the desired stereochemistry. After reductive cleavage of the NeO bond in isoxazoline 325 with zinc dust in acetic acid, a

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Scheme 58

Scheme 59

BaeyereVilliger oxidation of the resulting b-hydroxyketone 326 afforded lactone 327 in good yield. Facile indole formation was eventually carried out from 327 utilizing a radical cyclization reaction of an o-alkenylthioanilide, and then macrocyclization of the 2-nitrobenzenesulfonamide intermediate to afford 328. The crucial coupling of the upper half of the alkaloid

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with synthetic vindoline was successfully performed to furnish the coupling product in nearly quantitative yield, and subsequent transformations provided (þ)-vinblastine (329).

9. ASYMMETRIC REACTIONS OF 1,3-DIPOLES While the application of various dipolar cycloadditions to the synthesis of natural products has generated significant attention, the development of catalytic asymmetric methods has also proved fruitful. Diazoalkane cycloadditions, for example, have garnered a lot of interest. The Matsuoka lab demonstrated that titanium BINOL-ate complexes promote an enantioselective cycloaddition of diazoacetates to acrolein derivatives with modest yield but good to excellent enantioselectivities. For example, the addition of 330a with 331a was promoted by 10 mol percent of a 2:1 (S)-BINOL:Ti(OiPr)4 complex to give 332a in 52% yield and with 91% enantiomeric excess (Scheme 60) (2006JACS2174). Under similar catalytic conditions, the reaction of 330a with 331b afforded 332b in 63% yield and with 82% ee, and the reaction with 331c furnished 332c in 82% yield and with 92% ee. This methodology was applied to the enantioselective synthesis of manzacidin A (336). In this example, catalytic amounts of bis{((S)-binaphthoxy)(isopropoxy)titanium} oxide mediated the cycloaddition of ethyl diazoacetate (330b) with 331a to give 332d in 52% yield and with 95% enantiomeric

Scheme 60

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Scheme 61

excess. The reduction of the aldehyde functionality in 332d by the action of NaBH4 and reaction of the resulting alcohol with methyl orthoformate under acidic conditions gave 333 in 65% yield over two steps. Exposure of 333 to Raney-Ni and H2 provided an 85:5 mixture of 334 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 334 with 335 furnished 336 in 50% yield from 333. Building upon Maruoka’s work, Ryu’s group explored the use of chiral oxazaborolidinium ion 337 to catalyze the cycloaddition of diazoacetates with acrolein derivatives (2009CC5460). In this case, catalyst 337a (20 mol%) mediated the cycloaddition of 330b with 331a to give 332d in 87% yield and 91% ee (Scheme 61). Likewise, the reaction with 331c produced 339a in 97% yield and with 92% ee. In both of these cases, the enantioselectivities are similar to those involving Maruoka’s BINOL-ate catalyst, but the yields are significantly improved. In the case where R1 ¼ Bn (338a), the use of catalyst 337a led to the isolation of 339b in 72% yield, but with only a 76% ee. Alternatively, the use of catalyst 337b improved the enantioselectivity, producing 339b in 72% yield and 91% ee. Disubstituted acrolein derivatives also performed well. Dimethyl acrolein (338b), for example, reacted with ethyl diazoacetate in the presence of 337a to give 339c in 93% and with 92% ee. Five-membered ring aldehyde 338c reacted to give 339d in 73% yield and with 97% ee, while the six-membered ring 338d afforded 339e in 75% yield and in 92% enantiomeric excess. Sibi and coworkers used chiral magnesium complexes to promote the enantioselective addition of diazoacetates to electron-deficient alkenes

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Scheme 62

(2007OL1553). For example, the reaction of ethyl diazoacetate with 340a in the presence of Mg(NTf)2 and 341 at 20  C produced 342a in 72% yield with a 99% ee (Scheme 62) (2007OL1553). A variety of a,b-unsaturated amides gave good yields and excellent enantiomeric excess. The reaction with 340b, which contains a second carbonyl conjugated to the dipolarophile, gave 342b in 91% yield and 99% ee under similar conditions, while the more sterically demanding 340c reacted with the magnesium complex of 341 at rt to provide 342c in 79% yield and 98% ee. An aryl substituent also gave good chemical yield, though the enantioselectivity was somewhat lower. The magnesium complex-mediated reaction of 340d with 330b at 40  C furnished 342d in 76% yield but with 88% ee. More highly substituted alkenes were also reactive, though the yields were significantly reduced. Ethyl diazoacetate, for example, reacted with 343 to afford 344 in 61% yield but with 99% ee. After considerable experimentation, the Suga group found conditions that employ chiral Ni(II) catalysts to facilitate enantioselective cycloadditions. The substrates that worked best were the same general pyrazolidinone derivatives used in Sibi’s work. Ethyl diazoacetate (330b) added to 340a in the presence of a complex formed between Ni(BF4)2$6H2O and 345a at 45  C to give a mixture (85:15) of 342a and isomer 346a in 87% yield (Scheme 63) (2011JOC7377). The stereoselectivity of the reaction was excellent, with 342a being produced with 97% enantioselectivity. Alternatively, reaction of 340e with 330b mediated by the nickel-345b complex at rt produced only isomer 342e in 94% yield with 93% ee. The use of the catalyst derived from 345a also promoted the reaction, though in slightly

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Scheme 63

diminished yield (87%). The counterion of the Ni(II) complex also affected the enantioselectivity, with BF 4 generally giving better results. In the case of 340f, however, the reaction with 330b was best promoted using Ni(ClO4)2 to form the catalytic complex with 345b, furnishing 342f in 92% yield and 85% ee. Importantly, substituted diazoacetates also produced cycloadducts. The reaction of 347a with 340a in the presence of 345a and Ni(ClO4)2 gave 348a in only 15% yield and 70% ee and the remainder of the products corresponded 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, diazo ester 347b gave 348b in 73% yield and 75% ee under similar conditions. 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). Allyl alcohol, for example, reacted sequentially with Et2Zn (1.6 eq), (R, R)DIPT (0.2 eq), I2 (1.4 eq), pyridine N-oxide (1 eq) at 0  C, and this was followed by a subsequent addition of nitrone 350 to give 352a in 69% yield and with 98% ee (Scheme 64). Under similar conditions, 349b reacted to give 64% yield of 352b with >99% ee, though in this case it required higher equivalencies of reagents to induce reaction with 350. Alcohols 349c,d afforded 352c,d with >99% ee (48% yield) and 97% ee (63% yield), respectively.

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Scheme 64

Scheme 65

The OH group examined the ability of copper complexes with 355 (brucine diol) to effect a concerted [3 þ 2] cycloaddition between azomethine ylides derived from imines 353 and nitroalkenes 354 (Scheme 65) (2015OL1288). Schiff base 353a, obtained by the condensation of benzaldehyde and methyl glycine, reacted with 354a in the presence of 20 mol% each of CuOTf, 355, and DBN to give endo-adduct 356a as a single diastereomer in 97% yield and with 84% enantiomeric excess. Similarly, 356b was isolated in 92% yield and with 92% ee, and 356c was isolated in 92% yield and with 90% ee. The nitroalkene could be substituted with little impact on the diastereoselectivity or the enantioselectivity, with 356d being isolated in 92% yield and in 92% enantiomeric excess. The presence of a methyl group in 353d reduced the yield slightly (76%), but the enantioselectivity was still excellent (94% ee). Finally 353e containing a heteroaryl substituent produced an 18:1 mixture of endo- and exo-diastereomers, predominating in 356f, in 94% yield and with 84% ee when reacted with 354a in the presence

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of the copper complex and DBN. A stepwise reaction mechanism, wherein a conjugate addition of the reactive azomethine ylide to the nitroalkene occurs first followed by a subsequent Mannich-like cyclization, was ruled out by studies that showed the second step of such a mechanism is too slow to account for the rate of the reactions catalyzed by the copper-355 complex. Fukuzawa and coworkers showed that AgOAc and 357 promoted the reaction of 353 and 354 to give predominantly endo-adducts 356 in good yields and excellent stereoselectivities (Scheme 65) (2016TinPress). For example, 356a was produced (94:6 dr) in 70% yield and with 96% ee. Pyrrolidines 356b,c, and f were formed in 71e80% yields and with enantiomeric excesses ranging from 91% (356f) to 97%. In these cases, the catalyst loading was only 5 mol%. Sansano and coworkers, however, demonstrated that 358 and either Cu(OTf)2 or Ag(I) salts in the presence of Et3N effected the cycloaddition, also at a 5 mol% catalyst load, but with the opposite diastereoselectivity (2015S934). For example, 353a reacted with 354a in the presence of AgOBn, 358, and Et3N to give a 91:9 mixture of exo- and endo-diastereomers, this time favoring exo-356a. The exo-adduct was isolated in 88% yield and with >98% enantiomeric excess. Similar diastereoselectivities, yields, and enantioselectivities were observed for a variety of substituted imino esters and nitroalkanes. When reacted with 359 in the presence of CuBF4 and chiral bisphosphine 360 (3 mol% each), 353a gave spirocycle 361a in 83% yield and with 99% ee (Scheme 66) (2013CC9642). Varying the electronics of the

Scheme 66

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Scheme 67

aryl substituent did not affect the reaction; imino esters 353f,g underwent cycloaddition in the presence of the copper complex to produce 361b,c in 80% and 85% yield, respectively, and with 99% enantiomeric excess in both cases. Alkyl-substituted imino esters participated in the cycloaddition, but the yields were poorer. Imine 353h reacted with 359 under the standard conditions to afford 361d in 62% yield, and the enantioselectivity was still excellent (99% ee). 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 362, aldehydes 363a, and alkyne 364a were reacted in the presence of CuOAc, Ph-pybox 365, diacid 366, and 4  A molecular sieves to give a >95:5 mixture of 367b and the corresponding alkyne addition product 368 in 95% yield and with 99% ee (Scheme 67) (2013JACS11473). Under these conditions, various aldehydes successfully participated, with 363b-d giving mixtures (>95:5) favoring 367bed in 96%, 87%, and 92% yield, respectively, with 96%, >99%, and 88% enantiomeric excesses, respectively. Variously substituted alkynes also provided similar mixtures (>95:5) in excellent yields and enantioselectivities (367e, 87% yield and 99% ee; 367f, 94% yield, 96% ee). It is not clear if these reactions are concerted or, as Kobayashi and coworkers

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Scheme 68

demonstrated (2012JACS20049), they are stepwise addition/cyclization reactions. Sibi and coworkers reported an exo-selective cycloaddition of 369a with 370a mediated by the copper complex of 371 that produced 372a in 90% yield with an 88:12 diastereomeric ratio and with 94% ee (Scheme 68) (2007OL1553). Similarly, 370b reacted under similar conditions to give only 372b in 79% yield and with 95% ee. Crotyl substituted 369b reacted with 370b to give 372c as a single isomer in 77% yield but with only a 67% ee. Compound 369b failed to react with 370a, even with 100 mol% of the copper complex. Inomata, Ukaji, and coworkers developed asymmetric methods for adding azomethine imines such as 370b to allylic alcohols with good enantioselectivities (2006BCSJ1069, 2008CL342, 2010H887), and they expanded the methodology to the more challenging homoallylic alcohols. The magnesium alkoxide derived from 373a reacted with 370b in the presence of (R,R)DIPT to provide 375a in 76% yield and with 93% enantiomeric excess (Scheme 69) (2010CL1036). Likewise, 374a and 374b reacted to give 375b,c in 72% and 87% yield, respectively, with 93% ee in each case.

Scheme 69

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Scheme 70

Azomethine imines derived from aliphatic aldehydes reacted with highly variable chemical yield, but with moderate to good enantioselectivities (63e83% ee). Under the standard conditions, the more highly substituted homoallylic alcohol 373b reacted with 370a to give 375d in 78% yield and with 95% ee. Suga’s lab examined the use of a Ni(II) complex to effect asymmetric azomethine imine cycloadditions. In one example, chloroform solutions of dipole 370a added to 377 in the presence of Ni(II) and 378, furnishing a 93:7 mixture of 379a and the cis-isomer 380a in 93% yield and with 97% ee (Scheme 70) (2007OL97). The electronic nature of the aryl group of the azomethine imine had little impact on the reaction. Compound 376a afforded an 80:20 mixture of 379b:380b, with 379b being produced with 90% ee. Alternatively, 376b furnish 379c and 380c (91:9 dr) in quantitative yield and with 379c having 95% ee. Heterocyclic substituents were successfully deployed with 376c returning mixtures predominating in 379d (64:36 dr) in 83% yield and 95% ee. Alicyclic derivatives proceeded with diminished yield and enantioselectivities with 376d giving 379e and 380e (82:18 dr) in 74% yield but with 379e being produced with only 74% ee. The sterically less demanding 370b reacted under similar conditions to give good yields and diastereoselectivities, but with low enantiomeric excess. Organocatalysts are also effective promoters of azomethine imine cycloadditions. 1,3-Dipolar cycloadditions of cyclic enones remain challenging

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Scheme 71

substrates for LUMO-lowering iminium-based catalysis. The Chen group, however, used the cinchona alkaloid-derived 383 to promote the addition of 370b with cyclic enone 382a in the presence of 2,4,6-triisopropylbenenesulfonic acid (TIPBA) to furnish 384a in 89% yield and with 90% ee (Scheme 71) (2007AC7667). Variously substituted aryl groups, such as in 374a and b, also participated in the reaction with 382a, giving 384b and c in 73% and 99% yield, respectively, and with 92% ee in both cases. Furyl-substituted 381 reacted with 382a to give 384d in 99% yield and 95% ee. The use of cyclopentenone 382b required 20 mol% of the catalysts but reacted with 370a to afford 384e with 90% enantiomeric excess, though in a somewhat diminished yield (78%). Similarly, seven-membered ring dipolarophile 382c underwent cycloaddition with dipole 374a in the presence of 10 mol% 383 to give 76% yield of 384f with 93% ee. Chen’s group also examined the use of catalyst 385 to promote the exoselective cycloaddition of 370b with iminium ions derived from a,b-unsaturated aldehydes in modest to good yields but with good to excellent enantioselectivity (Scheme 72) (2006ASC1818). Dipole 370b, for example, reacted with a mixture of aldehyde 211b (10 mol%) and TFA in aqueous THF to give an 81:19 mixture of diastereomers 387a (96% ee) and 388a in 85% yield. It is important to note the differences with reaction conditions between this experiment and those shown in Scheme 42, where the organocatalyst facilitates an inverse-demand cycloaddition reaction by raising the HOMO of the dipolarophile. In this case the catalyst contains a free hydroxyl group that can act as a hydrogen-bond donor (as opposed to catalyst 212, which is a silyl ether) and the reaction medium contains a significantly stronger acid (TFA vs. 2,4-dinitrobenzoic acid)dproducing a less reactive

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Scheme 72

Scheme 73

conjugate base. The use of longer-chain aldehydes led to somewhat diminished yields but excellent enantioselectivities, as demonstrated by the reaction of 370a with 386 that yielded 85% of an 85:15 mixture 387b (94% ee) and 388b. As with other examples using this dipolarophile, varying the electronic nature of the aromatic substituent did not significantly affect the stereoselectivities of the reactions. Azomethine imine 374a reacted with the iminum ion derived from 386 and 385 to produce an 88:12 mixture of 387c (92% ee) and 388c in 66% yield, and 374b reacted under similar conditions to afford an 83:17 mixture of 387d (95% ee) and 388d in 77% yield. Wang et al. used chiral bis-phosphoric acid 390 to construct spirocyclic oxindoles (Scheme 73) (2013CC6713). Reaction of 389a and 370b in the

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presence of 10 mol% 390 afforded 391a in 93% isolated yield with 98% ee. As with other reports, varying the electronic nature of the aryl substituent on the dipole (e.g., 374a,b or 381) did not significantly change the yields or enantioselectivities of the reactions. Neither did changing the substitution pattern on the oxindole dipolarophile. Compounds 389b,c underwent 390-mediated cycloaddition to provide 391b,c in 84% and 93% yields, respectively, with 96% ee in both cases. Similarly, 389d reacted to give 391d in 87% yield and with 99% enantiomeric excess.

10. CONCLUDING REMARKS The application of the dipolar cycloaddition of 1,3-dipoles for the synthesis of alkaloids as described in this report spans a broad spectrum of organic chemistry. The regio- and stereoselectivity of the 3þ2-cycloaddition reaction is now well established, making it an attractive strategic disconnection for synthetic design of various alkaloids. As is the case in all new areas of research, future investigations of the chemistry of these dipolar cycloadditions for natural product synthesis will be dominated by the search for asymmetric synthesis. Forthcoming developments will also depend on gaining a greater understanding of the mechanistic details of this fascinating and synthetically important process.

ACKNOWLEDGMENT AP is particularly grateful to the National Science Foundation (grant CHE-1057350) for generous financial support as well the Camille and Henry Dreyfus Foundation for a Senior Scientist award.

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