Homoallylic amines, synthesis

Scheme 1). Introduction of a jt bond into the molecular structure of 1 furnishes homoallylic amine 2 and satisfies the structural prerequisite for an aza-Prins transform.4 Thus, disconnection of the bond between C-2 and C-3 affords intermediate 3 as a viable precursor. In the forward sense, a cation ji-type cyclization, or aza-Prins reaction, could achieve the formation of the C2-C3 bond and complete the assembly of the complex pentacyclic skeleton of the target molecule (1). Reduction of the residual n bond in 2, hydro-genolysis of the benzyl ether, and adjustment of the oxidation state at the side-chain terminus would then complete the synthesis of 1. 

In 2001, the preparation of allylytterbium bromide and the synthesis of homoallylic alcohols using allylytterbium bromide were reported.39 393 Ytterbium metal was found to be activated by a catalytic amount of Mel at 0 °C in THF to produce allylytterbium bromide 66 (Equation (11)). The allylation reaction of a wide range of aromatic aldehydes and ketones proceeded at ambient temperature or less in good to high yields (Table 2). Imines also reacted with allylytterbium bromide to afford homoallyl amines (Table 3). 

The synthesis of optically active compounds by the diastereoselective reaction of allyltitanium reagents with chiral electrophiles has also been reported. The reaction of allyltitanium reagents with chiral imines proceeds with excellent diastereoselectivity, as shown in Eq. 9.28, thus providing a new method for synthesizing optically active homoallylic amines with or without a P-substituent [51,52],... 

The development of new methods for the synthesis of homoallylic amine derivatives is an important area of synthetic efforts. Homoallylic amines are extremely important compounds as biologically active molecules [1], The Lewis acid-mediated reactions of imines with allyl silanes are among the most efficient for... 

Table 8 Bismuth-mediated three-component allylation reaction synthesis of iV-protected homoallylic amines...

Cross-cyclization of epoxides with homoallylic amines is an easy way to access tetrahydropyran moieties, which form the core structure of many biologically important natural products such as avermectins, aplysiatoxin, oscillatoxins, latrunculins, talaromycins, acutiphycins, and apicularens. Even though many methods are available for the synthesis of this moiety [14—24], its importance and wide applicability demands further methods. 

Stereoselective synthesis of trans 4-chloro-2-substituted piperidines can be achieved by the reaction of epoxides and N-protected homoallyllic amines using BiCl3 as the Lewis acid catalyst (Fig. 3). This method furnishes very good generality with respect to various epoxides with a regioselectivity that favors the trans-... 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of natural products. However, enantioselective methods for homoallylamine are quite undeveloped. In 1995, Itsuno and co-workers reported the first example of enantioselective allylation of an imine (Scheme 7) [13]. The reaction of N-trimethylsilylbenzaldimine 19 with a chiral allylboron reagent 20 in ether at -78 °C afforded the corresponding homoallylamine 22 in 73% ee. 

Chiral addition of allyl metals to imines is one of the useful approaches toward the synthesis of homoallylic amines. These amines can be readily converted to a variety of biologically important molecules such as a-, / -, and y-amino acids. Itsuno and co-workers utilized the allylborane 174 derived from diisopropyl tartrate and cr-pinene for the enantioselective allylboration of imines. The corresponding iV-aluminoimines 173 are readily available from the nitriles via partial reduction using diisobutylaluminium hydride (DIBAL-H) <1999JOM103>. Recently, iV-benzyl-imines 176 have also been utilized for the asymmetric allylboration with allylpinacol boronate 177 in the presence of chiral phosphines as the chiral auxiliaries to obtain homoallylic A -benzylamines 178 in high yield and selectivity (Scheme 29) <2006JA7687>. 

The conventional procedure for the synthesis of homoallylic amines involves the allylboration of imines (generated in situ from the partial reduction of expensive and toxic nitriles). Recently, a practical and operationally simple protocol has been developed for the stereoselective formation of homoallylic amines starting directly from the... 

Asymmetric Catalytic Aminoalkylations New Powerful Methods for the Enantioselective Synthesis of Amino Acid Derivatives, Mannich Bases, and Homoallylic Amines... 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Acetals result from oxidative coupling of alcohols with electron-poor terminal olefins followed by a second, redox-neutral addition of alcohol [11-13]. Acrylonitrile (41) is converted to 3,3-dimethoxypropionitrile (42), an intermediate in the industrial synthesis of thiamin (vitamin Bl), by use of an alkyl nitrite oxidant [57]. A stereoselective acetalization was performed with methacrylates 43 to yield 44 with variable de [58]. Rare examples of intermolecular acetalization with nonactivated olefins are observed with chelating allyl and homoallyl amines and thioethers (45, give acetals 46) [46]. As opposed to intermolecular acetalizations, the intramolecular variety do not require activated olefins, but a suitable spatial relationship of hydroxy groups and the alkene[13]. Thus, Wacker oxidation of enediol 47 gave bicyclic acetal 48 as a precursor of a fluorinated analogue of the pheromone fron-talin[59]. 

Synthesis of homoallylic amines has been reported by a three-component coupling of aldimines, diiodomethane, and alkenylzirconocenes, in the presence of dimethylzinc (Scheme 28).296,296a The formation of homoallylic products is rationalized by the mechanism shown in Scheme 29. The //////-relationship of the final product is explained by a cyclic chair-like transition state. This type of homologation was used to form f, -dicyclop ropy I ruethylamines by a double C,C-cr-bond insertion into bicyclobutanes (Scheme 30).297 During the course of this cascade process, 10 C,C-bonds are formed, and the final product is isolated in one step with a high diastereoselectivity. 

Lewis acid-mediated nucleophilic additions to carbon-nitrogen double bond have been applied to the synthesis of homoallylic amines.1 3 Three-component syntheses of homoallylic amines starting from aldehydes, amines, and allyltributyltin are realized in the presence of Lewis acids such as La(OTf)3, Bi(OTf)3, LiClOa (Equation (47)).154-156... 

Numerous studies have dealt with different types of sulfur-containing hetero-dienophiles. Thus, hetero Diels-Alder reactions of N -sulfinyl dienophiles have been thoroughly studied by Weinreb et al. [454] the resulting cycloadducts represent useful and versatile intermediates in the synthesis of homoallylic amines [455] or pyrroles [456]. Further work using this type of S = N dienophiles... 

Akiyama T, Saitoh Y, Morita H, Fuchibe K (2005b) Adv Synth Catal 347 1523 Akiyama T, Tamura Y, Itoh J, Morita H, Fuchibe K (2006a) Synlett 2006 141 Arend M (1999) Asymmetric catalytic aminoalkylations new powerful methods for the enantioselective synthesis of amino acid derivatives, Mannich bases, and homoallylic amines. Angew Chem Int Ed Engl 38 2873-2874 Arend M, Westermann B, Risch N (1998) Angew Chem Int Ed Engl 37 1045 Avemaria F, Vanderheiden S, Brase S (2003) Tetrahedron 59 6785 Babu G, Perumal PT (1998) Tetrahedron 54 1627... 

Functionalized piperidines 165 and 166 for the synthesis of enantiopure homokainoids have been generated in excellent yields via a Rh-catalyzed cyclohydrocarbonylation reaction on both homoallylic amines 167 and homopropargylic amines 168 <07JOC9418>. 

Diastereoselective synthesis of homoallylic amines. The Diels-Alder adducts (2) formed from 1,3-dienes and 1 undergo basic hydrolysis to a single unsaturated sulfonamide (3) via a concerted rctro-cnc reaction. 

Laschat, S, Kunz, H, Carbohydrates as chiral templates Stereoselective synthesis of chiral homoallyl amines and p-amino acids, Synlett, 51-52, 1990. 

Panek and co-workers have demonstrated that crotylsilanes 217 and 343 react with a variety of electrophiles including aldehydes, a, ff-unsaturated ketones, acetals and imines under appropriate activation conditions (usually Lewis acidic) to form homoallylic ethers [149, 261], homoallylic alcohols [58, 150, 151], tetrahy-drofurans [262, 263], cyclopentanes [264], pyrrolidines and homoallylic amines [265] with high levels of enantio- and diastereoselectivity [12]. This review will focus on the reactions of crotylsilanes 217 with Lewis acid-activated acetals and aldehydes, and the application of these reactions to the synthesis of polypropionate natural products [266-271]. 

The reaction of imines with allyltributylstannane provides a useful route for the synthesis of homoallylic amines [40]. In the course of our investigations to develop new synthetic reactions in water, we have found that three-component reac-... 

Yamamoto et al., on the other hand, reported that a Ti-allylpalladium-TBAF cocatalyst system enables allylation of aromatic imines with allyltrimefhylsilane at room temperature [376]. As described in Scheme 10.131, this allylation would proceed via a transmetalation mechanism involving the bis-Ti-allylpalladium intermediate 121. The use of chiral 7r-allylpalladium complex 131 enables asymmetric synthesis of homoallyl amines wifh good enantioselectivity (Scheme 10.150). 

For the Sc(OTf)3-catalyzed allylation of imines, use of allyltriethylgermane instead of tetraallylgermane turned out to be more effective and homoallyhc amines were obtained in high yields. Because aldehydes were not reactive under these reaction conditions, a three-component synthesis starting from aldehyde, amine, and allylgermane was used and found to proceed smoothly, providing homoallylic amines in high yields (Scheme 11.10) [23]. 

Combined use of BF3-OEt2 and AcOH was found to be effective for allylation of aldimines. The catalyst system is also effective for the three-component synthesis of homoallylic amines starting from aldehyde, amine, and allylgermane (Scheme 11.11) [24]. 

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