1.3- Dipolar cycloaddition reactions alkaloids

Highly selective 1,3-dipolar cycloaddition reactions of nitrone (154) with acrylates have been used in the total syntheses of pyrrolizidine alkaloids, 7-deoxy-casuarine (572) and hyacinthacine A2 (573) (Scheme 2.263) (772). 

The reader was given a taste of the power of isomiinchnone dipolar cycloaddition chemistry in Section 10.2.1. As discussed by Potts (1) and Gingrich and Baum (10), the isomiinchnone ring system—a masked carbonyl dipole—is exceptionally reactive as a 1,3-dipole in 1,3-dipolar cycloaddition reactions. In the intervening years since these two excellent reviews the major research efforts in isomiinchnone chemistry have entailed synthetic applications to specific targets such as alkaloids and other natural and unnatural products. 

Triazines are trimers of unstable imines and may serve as imine precursors. Treatment of trimer of A1-pyrrol ine with a trimethylsilylmethyl triflate gives trimethylsilylmethyl-imonium triflate which may be desilylated by cesium fluoride, providing an ylid suitable for 1,3-dipolar cycloaddition reactions and constmction of the hexahydro-pyrrolizine framework.386 This strategy has been applied to prepare trachelanthamidine, supinidine and isoretronecanol alkaloids.387... 

Dipolar cycloaddition reactions of nitrones, prepared by the oxidation of suitable hydroxylamines, have been used in a number of alkaloid syntheses. The preparation of tetrahydropyridine /V-oxides by means of the oxidative cleavage of suitable bicyclic isoxazolidines has been studied in connection with projected syntheses of... 

The importance of fully or partially hydrogenated isoxazolo[2,3-a]pyridines as intermediates in the synthesis of stereochemically complex molecules, particularly alkaloids, has led to a continued high level of interest in their preparation. The route of choice remains the 1,3-dipolar cycloaddition reaction between a tetrahydropyridine A-oxide, that is a nitrone, and a dipolarophile. A number of methods for the production of the nitrone for in situ reaction have been developed. They include the oxidation of the secondary amine, piperidine, with hydrogen peroxide in the presence of... 

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

Intramolecular 1,3-dipolar cycloaddition reactions normally proceed efficiently to give bicyclic products and these reactions do not require the presence of an electron-withdrawing group on the dipolarophile. Thus, in an approach to the alkaloid sarain A, the aziridine 221 was heated to generate the intermediate azomethine ylide 222, and hence, after intramolecular cycloaddition, the pyrrolidine 223 (3.143). " An alternative method for the formation of the required azomethine ylide, and which avoids the need for the prior synthesis of an aziridine ring, uses the simple condensation of an aldehyde and a primary or secondary amine. Thus, in another approach to sarain A, addition of formaldehyde to the amine 224 resulted in the formation of the cycloadduct 226 (3.144). Notice that in both cases the... 

Using rw-chloroalkenes (e.g., 42) in 1,3-dipolar cycloaddition reactions, Pearson et al. described the synthesis of several alkaloids [20-22]. The reaction proceeds by an intramolecular cycloaddition of an azide onto an alkene, producing an intermediate triazohne. Fragmentation of the triazoUne and rearrangement to a monocyclic imine occurs, which is internally N-alkylated by the alkyl chloride, resulting in iminium ion 43. Reduction with sodium borohydride leads to the racemic lycorane (44). 

The use of Rh(II) catalysts for the formation of 1,3-dipoles from diazo compounds via rhodium-carbenoids has facilitated the use of the dipolar cycloaddition reaction in key steps in the preparation of natural products. The synthesis of aspidosperma alkaloids 227 and their derivatives is important because these alkaloids contain the highly functionalized vindoline nucleus which is found in... 

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 tt-bonds 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. 

The 1,3-dipolar cycloaddition reaction of pyridinium ylides (40) with 3-alkenyl oxindoles (41) yielded spiro-cycloadducts (42) related to oxindole alkaloids, such as strychnofoline (Scheme 12). The one-pot 1,3-dipolar cycloaddition of 3-arylsydnones with a,/ -unsaturated ketones formed 1,3,4-trisubstituted pyrazoles in refluxing dry dimethylbenzene. ... 

For the diazoacetates, Mamoka and coworkers reported on the chiral titanium BINOLate-catalyzed highly enantioselective 1,3-dipolar cycloaddition reactions between diazoacetates and monodentate a-substituted acroleins, which give 2-pyrazolines with an asymmetric tetrasubstituted carbon center in 2006 (Table 7.6) [23], The titanium BINOLates, such as (5)-BlNOL/Ti(OPr )4 (2 1 molar ratio) complex (TB-b) and bis (5)-binaphthoxy)(isopropoxy)titanium oxide (TB-c), showed good results in terms of yields and enantiose-lectivities compared with simple (5)-BINOL/Ti(OPr )4 (1 1 molar ratio) complex (TB-a). The synthetic utility of the present reaction was further demonstrated by the total synthesis of a bromopyrrole alkaloid manzacidin A (Scheme 7.13), which was isolated firom the Okinawan sponge Hymeniacidon sp. [24],... 

The fact that dipolar cycloaddition reactions lead to the rapid assembly of a variety of heterocycles spurred considerable interest in the development of asymmetric processes controlled by chiral auxdiaries [23, 30, 34). Early investigations in this area showcased the use of menthyl [68] and phenethyl [23, 69] derivatives as chiral auxiliaries in nitrone cycloadditions. A notable example of the latter was reported by Baldwin (Scheme 18.13) [70], The cycloaddition reaction of 59 was observed to proceed with high induction to afford 60 in 70% yield (dr= 16 1). This adduct served as a key intermediate in synthetic studies directed towards the antitumor and antiviral alkaloid pretazet-tine (61). 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

Vogel and Delavier (26) reported a synthesis of the 6-azabicyclo[3.2.2]nonane skeleton 130 using an intramolecular azide-alkene cycloaddition strategy (Scheme 9.26). When refluxed in xylene, the azide 126 underwent an intramolecular 1,3-dipolar cycloaddition with the internal alkene. Nitrogen extrusion and subsequent rearrangement led to a mixmre of compounds 128, 129, and 130. Reactions of azides with the double bond of dienes were also used in various total syntheses of alkaloids, and will be discussed later in Section 9.2.2. 

Alkenyl nitrones, having the alkene connected to the nitrone nitrogen atom, have been used in another approach to intramolecular reactions (231-235). Holmes and co-workers have this method for the synthesis of the alkaloid (—)-indolizidine 209B 137 (210,231). The alkenyl nitrone 134, was obtained from the chiral hydroxylamine 133 and an aldehyde. In the intramolecular 1,3-dipolar cycloaddition, 135 was formed as the only isomer (Scheme 12.45). The diastereofacial selectivity was controlled by the favored conformation of the cyclohexane-like transition state in which the pentyl group was in a pseudoequatorial position, as indicated by 134. Further transformation of 135 led to the desired product 137. 

Oppolzer et al. (321) applied his own sultam as the auxiliary for a cychc nitrone in the synthesis of (—)-allosedamine (Scheme 12.60). The enantiomerically pure nitrone 209 was synthesized from 208 by base treatment, attack of the enolate on 1-chloro-l-nitrosocyclohexane at the nitrogen atom, and subsequent elimination of chloride. Subsequent addition of aqueous HCl gave the cyclic nitrone 209. The nitrone participated in a 1,3-dipolar cycloaddition with styrene, proceeding with complete exo-specificity. The product, 210, was obtained with a de of 93%. Two further reaction steps yield the piperidine alkaloid ( )-aUosedamine 211 in an overall yield of 21%. 

The 1,3-dipolar cycloaddition of nitrones to alkenes has been shown to be very useful in the field of synthesis of alkaloids. The reaction is normally efficient and the inherent features of carbon-carbon bond formation, oxygen transfer and nitrogen incorporation have been joined by high regioselectivity and even stereoselectivity (79ACR396). The... 

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