Use of oxygenated 1,3-dipoles for the synthesis of nitrogen containing heterocycles

Over the past several decades, the 1,3-dipolar cycloaddition reaction has been successfully applied in alkaloid synthesis as a strategy to reduce the number of steps, increase overall yield and employ more easily available starting materials. This mini-review presents selected examples making use of substituted carbonyl ylides as 1,3-dipoles for the preparation of numerous nitrogenous natural products. The cycloaddition reactions of mesoionic oxazolium ylides (isomünchnones) are first discussed, wherein intramolecular reactions of these dipoles have been exploited as an approach to the ring system of several different alkaloids. The creation of carbonyl ylide dipoles from the reaction of  -diazo compounds with either ketones, esters or amides in the presence of Rh(II) catalysts has significantly broadened their applicability for natural product synthesis and is reviewed here. The cases presented demonstrate that a domino cascade strategy of these unique ‘ push-pull’ dipoles may play a major role in shaping the future synthesis of complex nitrogen-containing natural products.


Introduction
In 1960 Rolf Huisgen introduced the concept of 1,3-dipolar cycloadditions providing five-membered ring heterocycles. 1In subsequent studies, his research team demonstrated that the (3+2) cycloaddition of a variety of 1,3-dipoles with alkenes, alkynes, and heteroatom-containing dipolarophiles provided a broad spectrum of nitrogen heterocycles. 13][4] These dipolar cycloadditions are also extremely useful for the synthesis of natural products such as alkaloids and other biologically important structures employing rather simple starting materials.In addition, dipolar cycloadditions using chiral substrates for asymmetric synthesis has been extensively explored since the 1990s. 5Because several reviews and related articles have been published dealing with the synthetic aspects of dipolar cycloaddition chemistry for the preparation of natural products, 6,7 this mini-review acknowledging the many contributions made by Peter Jacobi is intended to provide a selective rather than an exhaustive survey of the use of carbonyl ylide dipoles for alkaloid synthesis.

Carbonyl Ylides via Rh(II)-Catalysis of Diazo Compounds
][16] The ease of generating the 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. 17,18When 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.

Mesoionic Carbonyl Ylide Systems
Mesoionic oxazolium ylides (isomünchnones) 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.Isomünchnones are readily obtained through the transition metal catalyzed cyclization of a suitable -diazoimide precursor. 19The starting diazoimides are easily constructed by acetoacylation 20 or malonylacylation 21 of the corresponding amides which are then subjected to standard diazo transfer techniques. 22The first successful preparation and isolation of an isomünchnone induced by a transition metal process was described in 1974. 23Heating a sample of diazoimide 4 (R 1 and R 3 = aryl, R 2 = methyl) in the presence of a catalytic amount of Cu 2 (acac) 2 afforded a red crystalline material which precipitated from the reaction mixture (Scheme 2).The red solid was assigned as isomünchnone 5 on the basis of its spectral data and elemental analysis.Mesoionic ylide 5 was found to be air stable for several weeks and its overall stability was attributed to its dipolar aromatic resonance structure.Formation of the isomünchnone ring can be rationalized by initial generation of a metallo-carbenoid species which is then followed by intramolecular cyclization onto the neighboring carbonyl oxygen to form the mesoionic dipole. 24hese reactive dipoles can then be trapped with a variety of dipolarophiles to give cycloadducts in high yield.

Tandem cyclization/cycloaddition/cationic -cyclization protocol
6][27] The 1,3-dipolar cycloaddition of isomünchnones derived from -diazoimides of type 6 provides a uniquely functionalized cycloadduct (i.e.7) containing a 'masked' N-acyliminium ion (Scheme 3). 28By incorporating an internal nucleophile on the tether, annulation of the original dipolar cycloadduct 7 would allow 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 6, a tandem cyclization cycloaddition cationic -cyclization protocol was established as a method for the construction of complex nitrogen polyheterocycles of type 8. Scheme 3

Approach to the quinoline ring system of the ergot alkaloids
A number of approaches to complex alkaloids have been reported in which the intramolecular cycloaddition reactions of a transient isomünchnone dipole feature as the pivotal step for assembling the polycyclic frameworks.Thus, intramolecular reactions of isomünchnone dipoles generated from a series of alkenyl-and alkynyl-substituted diazoimides have been exploited as an approach to the quinoline ring system (rings C and D) of the ergot alkaloids (e.g., lysergic acid, 12).In one example, the Rh 2 (OAc) 4 -mediated tandem cyclization/cycloaddition sequence from diazoimide 9 led to cycloadduct 10 in very good yield (Scheme 4). 28he polycyclic adduct 10 was readily elaborated to 11 en route to ergot alkaloids via BF 3 .OEt 2 -mediated ether bridge cleavage and a Barton/McCombie deoxygenation sequence.Further attempts toward lysergic acid 12 were, however, thwarted due to the inability to isomerize the trisubstituted double bond in 11.
Thus, N-malonylacylation of the precursor amide was carried out followed by a standard diazo transfer reaction to produce the requisite -diazoimide 13.The reaction of 13 with a Rh(II)-catalyst gave cycloadduct 14, which underwent a TMSOTf catalyzed ring opening to furnish enamide 15 in 78% yield.With the ringopened lactam in hand, a Barton-McCombie deoxygenation reaction 31 delivered 16 in 88% yield.Utilization of a sequential saponification/decarboxylation protocol afforded enamide 17. 32 This sequence constitutes a formal synthesis of (±)-vallesamidine 18, based on the successful conversion of 17 into 18 by Heathcock and co-workers. 30

(±)-Lycopodine
Another application of the domino cascade process toward the construction of alkaloids involved the synthesis of (±)-lycopodine 23 (Scheme 6). 33The isomünchnone cycloadduct 20 was formed from the Rh(II)-catalyzed reaction of diazo imide 19 and was found to be the precursor of the key Stork intermediate 22 (via 21).7][38] The rearranged product 21 was then converted into the key intermediate 22 previously used by Stork for the synthesis of (±)-lycopodine 23. 33Scheme 6

Indolizidine alkaloids
A further implementation of the cascade methodology involves the efficient assembly of the indolizidine ring system by using the Rh(II)-catalyzed [3+2]-dipolar cycloaddition of the phenylsulfonyl substituted diazopyrrolidinone 24 with an appropriately substituted dipolarophile (Scheme 7).The resulting pyridone 27 represents a very versatile synthon.0][41][42] The C 6 hydroxyl substituent, protected as triflate 28, allows for an assortment of cross coupling-possibilities.The versatility of the method was demonstrated by the synthesis of the angiotensin converting enzyme inhibitor (-)-A58365A 29, (±)-ipalbidine 30, -carbolinone 31 and a variety of other novel indolizidine-based compounds. 42Scheme 7

Mappicine ketone
An efficient synthesis of the naturally occurring oxoindolizino quinoline mappicine ketone 37 has been carried out by Greene and coworkers by making use of pyridone 32a as a key intermediate. 43The synthesis of 37 began with formation of the known cycloadduct 32a (R 1 = H; R 2 = CO 2 Me) by cycloaddition of the isomünchnone dipole derived from diazo sulfone 24 with methyl acrylate (Scheme 8). 39This multistep sequence proceeded smoothly and in high yield when catalyzed by rhodium(II) acetate.Hot aqueous hydrobromic acid then effected decarbomethoxylation of 32a to give 32b in 82% yield.Etherification of 32b with commercially available (E)-1-bromo-2-pentene and cesium carbonate in dimethylformamide produced the expected substitution product 32c, which cleanly underwent a Claisen rearrangement in refluxing chlorobenzene to afford the desired rearranged derivative 33 in 74% overall yield.This transformation is a rare example of a Claisen rearrangement taking place in a hydroxypyridone system. 44,45The -hydroxypyridone 33 was then converted into its triflate derivative under standard conditions.This was followed by Stille coupling with tetramethyltin to provide -methyl pyridone 34 in 84% yield.In the presence of rhodium(III) chloride in hot ethanol, compound 34 was rapidly isomerized to olefin 35a (91%).The success of this key transformation derives from the carbon symmetry of the -substituent in pyridone 34.Oxidation of 35a in two steps then selectively generated the Friedländer substrate 35b, which was reacted with o-aminobenzaldehyde to give oxoindolizino-quinoline 36 in 73% yield.Ozonolysis of 36 in CH 2 Cl 2 /MeOH at -78 o C accomplished selective double-bond cleavage in 36 to provide mappicine ketone 37. Scheme 8

(±)-Camptothecin
A related synthesis of racemic camptothecin 38 was also carried out by Greene and coworkers soon thereafter and is similarly based on the isomünchnone dipole strategy. 46The starting point commenced from the readily available hydroxyl-pyridone 32b (Scheme 9).Subsequent steps include a Claisen rearrangement of a functionalized allylic ether, a hindered Heck coupling, and a Friedländer condensation.

Atorvastatin
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 ( 46) 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.Gribble and Lopchik described the preparation of 46 in seven steps from commercially available 4-fluorophenylacetic acid. 48The key step involved a 1,3-dipolar cycloaddition of the complex münchnone mesoionic heterocycle 45 with N,3-diphenylpropiolamide as shown in Scheme 11. 49,50 Scheme 11 AUTHOR(S) 4. 'Push-Pull' Carbonyl Ylide Systems

(±)-Aspidophytine
One of the early examples of the trapping of a non-heteroaromatic carbonyl ylide dipole with a tethered bond for alkaloid synthesis was found as the central step in an approach toward the complex pentacyclic alkaloid (±)-aspidophytine 51. 51,52]The key sequence of reactions involved a 1,3-dipolar cycloaddition of the 'push-pull' dipole 48 across the indole -system.The exo-cycloadduct 49 was the exclusive product isolated from the Rh(II)-catalyzed reaction of 47 (Scheme 12).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 lesscongested exo face.Treatment of the resulting dipolar cycloadduct 49 with BF 3 .OEt 2 induces a domino fragmentation cascade.The reaction proceeds by an initial cleavage of the oxabicyclic ring and formation of a transient N-acyliminium 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 50.Subsequent functional group manipulations allowed for the high-yielding conversion of 50 into (±)-aspidophytine 51.

Kopsifoline alkaloids
As a further extension of 'push-pull' dipole cycloaddition chemistry, the Rh(II)-catalyzed cyclization / cycloaddition cascade was applied toward the hexacyclic framework of the kopsifoline alkaloids.Using the metal-catalyzed domino reaction as a key step, the heterocyclic skeleton of the kopsifolines (52) could eventually be built by a 1,3-dipolar cycloaddition of a 'push-pull' carbonyl ylide dipole derived from -diazo ketoester 53 across the indole π-bond.Ring-opening of the resulting cycloadduct 54 followed by a reductive dehydroxylation step produced the critical silyl enol ether 55 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 52 could readily be constructed by the proposed sequence of reactions outlined in Scheme 13. 53,54 The isolation of 54 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 54 followed by a reductive dehydroxylation step resulted in the formation of the silyl enol ether 55 necessary for the final F-ring closure of the kopsifoline skeleton (i.e., formation of 56).Scheme 13

(±)-3H-Epivincamine and (±)-tacamonine
The total synthesis of several members of the vinca and tacaman class of indole alkaloids has also been accomplished using 'push-pull' dipoles in the critical cycloaddition step. 55,56The central step in the synthesis consists of an intramolecular [3+2]-cycloaddition reaction of -diazo indoloamide 57, which delivers the pentacyclic skeleton of the natural product in excellent yield (Scheme 14).

Scheme 14 AUTHOR(S)
The acid lability of the oxabicyclic structure was exploited to establish the trans-D/E-ring fusion of (±)-3Hepivincamine 60.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 60 was also employed for the synthesis of the tacaman alkaloid (±)-tacamonine 61.

(-)-Vindoline
8][59][60][61] This unique domino cascade was used to assemble the fully functionalized pentacyclic ring system of vindoline 66 in a single step that forms four C-C 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 15).The reaction leading to 65 is initiated by an intramolecular inverse electron demand Diels-Alder cycloaddition of the 1,3,4-oxadiazole 62 with the tethered enol ether.Loss of nitrogen from the initial Diels-Alder cycloadduct 63 provides the 'push-pull' carbonyl ylide 64, which then undergoes a subsequent 1,3-dipolar cycloaddition with the tethered indole.Importantly, the diene and dienophile substituents complement and reinforce the [4+2]-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 [3+2]-cycloaddition sterically directed to the R-face opposite the newly formed fused lactam.This endo diastereoselection for the 1,3-dipolar cycloaddition has been attributed to a conformational (strain) preference dictated by the dipolarophile tether. 59Cycloadduct 65 was eventually transformed into the natural product vindoline 66 in several additional steps.Extension of these cascade studies by the Boger group also provided for a total synthesis of the bis-indole alkaloids vinblastine and vincristine. 61

Conclusions
The application of the cycloaddition of carbonyl ylide dipoles for the synthesis of alkaloids as described in this mini-review spans a broad spectrum of organic chemistry.The regio-and stereoselectivity of the 3+2cycloaddition reaction is now well established, making it an attractive strategic disconnection for synthetic design of various nitrogenous natural products.As is the case in all new areas of research, future investigations of the chemistry of these dipolar cycloadditions of carbonyl ylides for heterocyclic synthesis will be dominated by the search for new asymmetric processes.Future developments will also depend on gaining a greater understanding of the mechanistic details of this fascinating and synthetically important process.

Acknowledgments
AP is particularly grateful to the National Science Foundation, the National Institute of Health and the Camille and Henry Dreyfus Foundation for generous financial support over his career.