Indolizidines, examples

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

A novel approach to azabicyclic ring systems, based on an epoxide-initiated electrophilic cyclization of an alkyl azide, has been developed by Baskaran. A new stereo- and enantioselective synthesis of the 5-hydroxymethyl azabicyclic framework 91a, present in (+)- and (-)-indolizidines 167B and 209D, for example, was... 

A review article is an intensive survey of a rather narrow field for example, the titles of some recent reviews are Desulfonation Reactions Recent Developments , Pyrrolizidine and Indolizidine Syntheses Involving 1,3-Dipolar Cycloaddtion , and From Corrin Chemistry to Asymmetry Catalysis—A Personal Account. A good review article is of enormous value, because it is a thorough survey of all the work done in the field under discussion. Review articles are printed in review journals and in certain books. The most important review journals in organic chemistry (though most are not exclusively devoted to organic chemistry) are shown in Table A.3. Some of the journals listed in Table A.l, for example, the Bull Soc. Chim. Fr. and J. Organomet. Chem. also publish occasional review articles. 

A variety of cyclic olefins (5-, 6-, and 7-membered) that contain nitrogen have been prepared via ring-closing metathesis, for example as shown in Eq. 33 [209]. Other examples are shown in Eqs. 34 [210] and 35 [211]. A variety of pyrrolizi-dines, indolizidines, quinolizidines, pyrrolidinoazocines, piperidinoazocines, and other fused nitrogen heterocycles have also been prepared via ROM (e.g., Eq.36 [212,213]). 

Alkyl azides have been involved in the synthesis of indolizidinone derivatives in several ways. One example (Scheme 7) is the intramolecular Schmidt reaction between alkyl azides and ketones which can be used to transform azidoketone 24 into the corresponding indolizidinones 26 through intermediate 25 <2001JOC886> or with epoxides to obtain the indolizidine 27 <2004JOC3093>. 

Reactions where the reduction of a functionalized nitrogen, or the deprotection of an amine group, start a domino process with the sequential formation of the two rings of the indolizidine system, find many examples in the literature. A recent one is provided by the synthesis of (—)-indolizidine 223AB <20040L1493> (Scheme 10). 

Several other examples are reported in the literature on the synthesis of indolizidine skeleton through the intramolecular nucleophilic attack of the six-membered ring nitrogen atom onto an electrophilic center such as an alkyl halide <20000L3861, 1997S95>, triflate <20010L711>, and esters <1998TL5693>. 

Due to the widespread presence of the indolizidine skeleton in many natural products, both the procedures aimed at the functionalization and elaboration of the ring are also of interest. A clear example of this is represented by the elaboration of indolizidinone 184 that was transformed into several different polyhydroxy or alkylated products (Scheme 44) <1995JOC398>. 

Pyridinium salts tethered to ketones also undergo cathodic cyclization [1]. The reaction provides a convenient diastereoselective route to quinolizidine and indolizidine derivatives such as 203, 204 and 206, 208, and 209, and appears to hold significant promise as a route to alkaloids. Examples are portrayed and the optimal conditions are listed below the equations. A mercury cathode is preferred, as passivation occurs when lead is used, and the reaction does not occur... 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

Much work has been done on the reactions of indolizidine immonium salts, which has been reviewed to some extent <78AHC(23)103). A general view may be obtained using Scheme 14, the chemistry of indolizidine itself being taken as an example. 

Reductive cyclizations have been frequently used to obtain indolizidines (78AHC(23)103). The route shown in Scheme 27 is an example. 

Indolizidine is the alkaloid S-coniceine and this nucleus has been observed in several groups of alkaloids. Since the chemistry of alkaloids deriving from indolizidines and partially unsaturated indolizidines is reported regularly (B-81MI30800, B-79MI30800), only selected examples will be taken from the natural products field. Structurally more complex alkaloids such as (217), (218) and indolizidine aza steroids (81H(16)1093,81H(16)1097), which may often be assigned to other groups of alkaoids as well, are not mentioned. 

Some heteropolycycloalkanes, e.g. indolizidine, quinolizidine, tropane, and decahydro-quinoline, are parent skeletons of alkaloids. Carbon-13 shifts of these and other parent polycycloalkanes [408] (Tables 4.64 and 4.65) are predominantly determined by heteroatom electronegativity, ring size, stereoisomerism, and dynamic effects. Aza- and thiade-calins are representative examples (Table 4.64). As described for cis- and trans-decalin (Section 4.1.3), carbon nuclei in the cis isomers of aza- and thiadecalins are shielded... 

Although the indolizine nucleus appears not to occur naturally, its perhydro derivative, commonly named indolizidine, is the alkaloid 8-coniceine, and this nucleus is to be found in several groups of alkaloids including those from the plant groups Ipomoea, Elaeocarpus, Tylophora, Amaryllidaceae, and Orchidaceae. Since the chemistry of these alkaloids has been reviewed regularly,1 only selected examples will be taken from the natural products field. 

Diazoacetamides are also exceptional substrates for dirhodium carboxamidate-catalyzed reactions, although with these substrates a mixture of /3-lactam and y-lactam products are formed [8]. The rhodium carboxamidate catalyst can have a major effect on the ratio of products formed. A good synthetic example is the Rh2(4S-MPPIM)4)-catalyzed synthesis of (-)-hcliotridanc 11 (Scheme 5) [9]. The key C-H insertion step of 9 generated the indolizidine 10 in 86 % yield and 96 % de, whereas reaction of 9 with achiral catalysts tended to favor the opposite diaster-eomer. 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

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