Spirocycles, stereoselectivity

The intramolecular cycloaddition of the norbornadiene-tethered nitrile oxides 110 (Eq. 11 and Table 11) was reported to be highly regio- and stereoselective, providing the exo cycloadduct 111 as the exclusive product out of the four possible regio/stereoisomers [36]. The cycloadduct 111 provides a stereoselective entry into tricyclic (e.g., 112) and spirocyclic (e.g., 113) frameworks. 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

If the side chain with the nucleophile is situated in the 1-position of the conjugated diene, a palladium-catalyzed spirocyclization occurs. In this case stereoselective oxa-spirocyclizations were obtained from the diene alcohols 59 and 60 (equation 23 -25)58. The reaction worked well for the formation of a tetrahydrofuran and tetrahydropyran in the spirocyclization. In the absence of chloride ions 59 gave high yields of the acetoxy oxaspirocyclic compound 61 via a 1,4-anti addition across the diene (equation 23). In the presence of stoichiometric amounts of LiCl a 1,4-syn oxychlorination took place and allylic chloride 62 was obtained (equation 24). Under chloride-free conditions, cyclohep-tadiene alcohol 60 afforded oxaspirocyclic acetate 63 (equation 25). 

Vinylidenecycloalkanones 125 undergo cycloadditions with 1,3-dienes in the presence of a Lewis acid catalyst to give spirocyclic dienones 126 [107]. Good regio- and stereoselectivities were observed for unsymmetrical dienes. 

Since the migrating group retains its configuration, the use of enantiomerically enriched oximes provides a direct entry to enantiomerically pure lactams. These lactams may be used as a key building block for the synthesis of diverse compounds. Westermann and Gedrath applied this strategy to the stereoselective synthesis of enantiomerically pure o-.a-disubstituted a-amino acids (equation 135), bicyclic lactams and the spirocyclic framework of Histrionicotoxins (equation 136). 

S. Z. Dong and L. A. Paquette, Stereoselective synthesis of conformationally constrained 2 -deoxy-4 -thia beta-anomeric spirocyclic nucleosides featuring either hydroxyl configuration at C5, J. Org. Chem., 70 (2005) 1580-1596. 

Nucleophilic addition to the spirocyclic ketone also proceeds with high stereoselectivity. ... 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

The use of propargyl vinyl ethers prompted Toste et al. to develop a stereoselective preparation of 2-hydroxy-3,6-dihydropyrans, suitable for the synthesis of spirocyclic compounds. The reaction was catalyzed by a small amount (1 mol%) of [0(AuPPh3)3]... 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

A stereoselective, Lewis acid-mediated cyclization of l-substituted-2-naphthols (41) has been reported to produce spirocyclic ketones (43). Evidence has been presented for the involvement of the cyclic aluminium intermediate (42).50... 

Palladium-catalyzed reaction of bromo dienes 39 was complete after a few hours, and afforded spirocycles 40a and 40b as single regio- and stereoisomers (Scheme 12). The Heck spirocyclization reaction is regioselective, giving five-membered heterocycles. In addition, it is stereoselective because the Heck adducts were obtained as single geometric isomers [60]. 

Deshmukh et al. [134] have investigated the use of D-(+)-glucose derived chiral ketenes in the stereoselective synthesis of spiro-(3-lactams 226-227. The D-(+)-glucose acid chloride 224, serving as a ketene precursor, in the Staudinger cycloaddition reaction with appropriate imines 225 afforded the diastereomeric mixture of spirocyclic-(3-lactams 226-227 in 70 30 ratio, respectively. This reaction has cleanly produced only two diastereoisomers instead of theoretically possible four... 

In conclusion, the CAI activity of spiro-(3-lactams, their antiviral and antibacterial properties, their potential as efficient (3-tum nucleators and (3-tum mimetics, and their application as synthons for a,a-disubstituted (3-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic (3-lactams. Several approaches to the stereoselective synthesis of spiro-(3-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-(3-lactams. In addition, we have developed a facile route to novel spiro-(3-lactams by using... 

A stereoselective synthesis of substituted tetrahydrofurans (69) via Pd-catalysed reactions of aryl and vinyl bromides with y -hydroxy terminal alkenes (68) has been described. This transformation affords trans-2,5- and frara-2,3-disubstituted tetrahydrofurans with up to >20 1 dr. This methodology also provides access to bicyclic and (g) spirocyclic tetrahydrofuran derivatives in good yield with 10-20 1 dr. The effect of... 

The nucleophilic reaction of Grignard reagents with azetidin-2,3-dione 270 yielded mainly fA-3-hydroxyazetidin-2-ones 271 (Equation 76) <2006S115>. A regio- and stereoselective reaction of azetidine-2,3-dione 272 with an organoindium compound led to the formation of azetidin-2-one-tethered homoallylic alcohol 273 (Equation 77), which has been used as precursor of spirocyclic azetidin-2-ones <2004TL6429>. 

With the spirocycle in hand, a regioselective and stereoselective Heck reaction was used to install the substituted aromatic portion of the molecule (Scheme 28.5). It is interesting that the addition of water to the reaction provided the high selectivity. The remaining olefin was reduced over Pearlman s catalyst, and the protecting groups were removed to provide the desired NK-1 antagonist 14 in 7 overall steps.33... 

It is much more difficult to pass stereochemical information from one ring to the other in spirocyclic compounds because each ring is orthogonal to the other. Nonetheless, some reactions are surprisingly stereoselective—one such is the reduction of the spirocyclic diketone that we made a moment ago. Treatm it with 1-iAllI4 gives one diastereoisomer of the spirocyclic diol. 

Hydride abstraction from dienyl tricarbonyl iron complexes furnishes cationic dienyl tricarbonyl iron complexes. For example, reaction of the diene-iron tricarbonyl complex (115) with triphenyhnethyl hexafluorophosphate followed by trimethylsilyl cyanide furnished with excellent regio- and stereoselectivity a new diene iron tricarbonyl complex (116) (Scheme 170). Excellent regio- and stereoselectivity is seen upon reaction of the cationic complex (116) with trimethylsilyl cyanide (TMS-CN) (Scheme 170). Reduction of the nitrile affords a spirocyclic lactam complex. Intramolecular cyclization of in situ formed enols furnishes spirocyclic compounds again with excellent stereoconfrol (Scheme 171). An interesting example of hydride transfer from a cyclohexadiene ring to a pendant aldehyde followed by nucleophilic addition is seen in Scheme 172. 

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