5-Substituted indolizidines

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. 

In efforts designed to replace the imidazopyridine ring system, indolizi-dines such as (32) [101] (human H3 if = 13 nM), and related heterocycles [102-104] were identified as potent H3 antagonists. Indolizidine (32) suffered from rapid metabolism in human liver microsomes, however, substitution on the indolizidine ring suppresses this liability. 

SAM, samandarines BTX, batrachotoxins HTX, histrionicotoxins PTX, pumiliotoxins aPTX, allopumiliotoxins hPTX, homopumiliotoxins DHQ, 2,5-disubstituted decahydroquinolines 3,5-P, 3,5-d [substituted pyrrolizidines 3,5-1 and 5,8-1, disubstituted indolizidines 1,4-Q, 1,4-disubstituted quinolizidines Epi, epibatidine Pseudophry, pseudophrynamines. With the exception of 3,5-P and 3,5-1, these alkaloids are not known to occur in arthropods (see text). Histrionicotoxins may occur in Minyobates and Mantella, but the evidence is not conclusive. 

Finally, intramolecular Diels-Alder reactions, catalyzed by Lewis acids <1999TL7215> or thermally induced <1997JOC2093>, were used to obtain cyano-substituted indolizidine derivatives (Scheme 6). 

The extension of the Kulinkovich reaction to succinimide 75 gave a new entry into substituted indolizidines. Initially, it was demonstrated that reacting 75 under the Kulinkovich conditions, with terminal alkenes and... 

Often, in the synthesis of natural products containing the indolizidine substructure, it is necessary to modify a preformed indolizidine ring. This is the case in the synthesis of (+)-myrmicarin 217 191 where the key step is the closure of the third ring through an electrophilic substitution on the pyrrole nucleus (Scheme 45) <2000JOC2824>. 

Both pyrrolizidines and indolizidines may be similarly formed by cyclization at the less-substituted, internal position of trialkyl-substituted al-kene radical cations (Scheme 29) [139,143]. Related processes featuring exo-digonal radical cyclizations have also been described (Scheme 30) [139,141 — 143]. 

Mild conditions discovered for the cyclization of propargyl pyridine 145 were applied to other substituted and elaborated heterocydes, giving indolizidine-type products in good-to-excellent yields (Table 9.17). 

These authors also showed that the indolizidine skeleton can be prepared from cyclopropyl dipolarophiles (Scheme 1.16). The cycloaddition of alkyhdenecyclo-propanes 67 with various nitrones (e.g., 68) afforded the expected isoxazolidine adducts 69 and 70, commonly forming the C(5) substituted adducts 70 (97,105-108) predominantly but not exclusively (109-111). Thermally induced rearrangement of the spirocyclopropyl isoxazolidine adduct 70 afforded the piperidinones 71 (107,108). These authors propose reaction via initial N—O bond homolysis of 70 to diradical 72 followed by ring expansion through relief of the cyclopropyl ring strain forming the carbonyl of a second diradical intermediate 73, which cyclizes to afford the isolated piperidinone 71. 

Evidence for the configurations, i.e. the cis/trans relationship of a substituent with respect to the bridgehead hydrogen atoms, has also been presented. An a priori estimation of the relative stabilities of isomeric substituted indolizidines, assuming a trans junction between the rings, led to the conclusion that equatorial substituents in the six-membered ring and pseudo equatorial substituents in the five-membered ring are thermodynamically favoured. 

The immonium salt (98) on reaction with numerous nucleophiles yields 9-substituted indolizidines. From the reaction with benzylmagnesium chloride, (100 R = Ph) is obtained (100 R = C02Et) results from a Reformatsky reaction. Reaction of the bridgehead substituted indolizidines (100) with methyl iodide and base results in /3-elimination with ring opening, a nine-membered heterocycle (101) being formed. This type of reaction has been varied widely. 

Cyclization of P-allenylamine systems to six-membered ring products has been observed recently. Cyclization of terminally substituted p-allenylamides with silver tetrafluoroborate produced lactam products (equation 137).267 The cyclization shown in equation (138) was used to generate the indolizidine ring system of allopumiliotoxin alkaloids.2676... 

Stereoselective intramolecular conjugate addition reactions (Scheme 4) of dithiane anions tethered to an a,/ -unsaturated nitrile have been developed to advantage for the synthesis of axially substituted indolizidines and quinolizidines.81 The control of axial nitrile orientation by a peg-in-a-pocket template effect has been discussed. 

Enantiopure a, ft -unsaturated 5-lactams react stereoselectively with carbon-, nitrogen-, sulfur-, and oxygen-centred nucleophiles [N3-, Me(CH2)nS, MeO-, and n-Bu-]. The synthetic potential of these conjugate additions has been demonstrated through the synthesis of two new substituted indolizidines, (7/f)-7-amino-8-deoxy-swainsonine and (7/ )-7-acetylaminoswainsonin.133... 

The copper complexed aminyl radical cyclization has been used as a key step in a short total synthesis of ( )-gephyrotoxin 223AB (60). The alkenyl substituted ALchloropiperidine 59 was stereoselectively cyclized to construct the indolizidine ring system (Scheme 17) (86JOC5043). Tribu-... 

The Lewis acid-catalysed 3 + 2-cycloaddition of aziridine-2-carboxylates with isocyanates proceeds regio- and stereo-specifically to produce enantiomerically pure 4-substituted imidazolin-2-ones in high yields.33 The reaction of ethyl 7-iodo-2-heptynoate (27), 2-arylaziridines (28), and K2C03 produces polysubstituted indolizidines (30) via an S /formal 3 + 2-cycloaddition (29) process (Scheme 8).34... 

Nickel-catalyzed cyclization of a 1,3-diene side chain of the substituted pyrrolidones yields a precursor to the indolizidine alkaloid (—)-elaeokanine C (Equation 86) <1997TL3931>. Other metal-catalyzed reactions include the Rh-induced in situ carbene generation and subsequent cyclization onto the heteroatom to yield piperidines <1997T16565, 1997JOC67>. Pauson-Khand cyclizations have also been used (Equation 87) <1997T6611>. 

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