Diastereoselective spirocyclization

A crystal structure is available for the compound with R = HC=C(CH2)2, and a mechanism was also proposed. On changing the reaction conditions (CH3CN, 82°C) and using Af-propionylimidazole, a tricyclic imidazo[l, 2 l,2]pyrrolo[2,3-6]furan was obtained in a diastereoselective spirocyclization reaction tl59],[157]... 

The Kobayashi group has observed the intramolecular diastereoselective spirocyclization of racemic 2-haloindoles bearing a C3-tethered allylic alcohol [71, 72]. For example, CuCl-catalyzed intramolecular Ullmann coupling of 117 followed by spontaneous Claisen rearrangement of the intermediate pyranoindole 118 afforded, in a one-pot synthesis, the all-carbon quaternary center of spiro-oxindole 119 in 95% de (Scheme 31). The methodology has been extended to the synthesis of hexahydropyrroloindoles, e.g., ( )-debromoflustramine B and E. 

Scheme 10 Diastereoselective spirocyclization for the total synthesis of aranorosin...

The diastereoselectivity observed can be explained by a synclinal transition state, probably influenced by chelation and/or stereoelectronic effects of the developing cation38. The minor product is formed via an antiperiplanar transition state. All compounds obtained are useful precursors for several spirocyclic natural products, such as terpenes like lubimine or acoradi-ene. 

Oxidation of cyclic phosphonoformaldehyde dithioacetal, using the Modena protocol, yields the trans disulfoxide 121 in excellent enantiomeric excess. Then 121, via HWE olefination and oxidation of the double bond has been used for the diastereoselective preparation of spirocyclic his-sulfinyl oxiranes (new versatile intermediates in asymmetric synthesis) [79] (Scheme 37). 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

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]. 

Catalyst 70 is very effective for the reaction of terminal alkenes, however 1,1-disubstituted olefins provide hydrosilylation products presumably, this is due to steric hindrance [45]. When a catalyst with an open geometry (78 or 79) is employed, 1,1-disubstituted alkenes are inserted into C-Y bonds to give quaternary carbon centers with high diastereoselectivities (Scheme 18). As before, initial insertion into the less hindered alkene is followed by cyclic insertion into the more hindered alkene (entry 1) [45]. Catalyst 79 is more active than is 78, operating with shorter reaction times (entries 2 and 3) and reduced temperatures. Transannular cyclization was possible in moderate yield (entry 4), as was formation of spirocyclic or propellane products... 

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

In a stoichiometric reaction the 6jr-allyl)palladium complex 66 was isolated and characterized5815. In a subsequent reaction the jr-allyl complex was reacted with benzoquinone in acetic acid to give an allylic acetate, which was hydrolyzed and oxidized to theaspirone. Interestingly, a quite high diastereoselectivity for the turns methyl isomer was obtained in the palladium-mediated spirocyclization (equation 28). 

An intramolecular imino-ene reaction was used as the key step in the synthesis of the non-natural perhydrohis-trionicotoxin.90 The spirocycle 147 was obtained as a single diastereomer upon exposure of 145 to TiGl2(01Pr)2 (Scheme 31). The transition structure 146 was proposed to explain the high diastereoselectivity of this reaction. 

In a more complex elaboration of the hydrogen atom abstraction/nucleo-philic cyclization route to tetrahydrofurans (Scheme 20), a carbohydrate-based N-alkoxy phthalimide was converted to a spirocyclic acetal in excellent yield and diastereoselectivity (Scheme 33) [136]. In this cyclization, nucleophilic attack takes place from the endo face of the trioxabicyclo [3.3.0] octane... 

In another example, the cumulative effect of equatorial attack in prochiral cyclohex-anoneimines with diastereoselectivity induced by a chiral nitrogen substituent allowed the synthesis of spirocyclic oxaziridines with a high induction of axial dissymmetry. The major oxaziridine isomer results from both the favored equatorial attack and oxidation anti to the chiral nitrogen substituent (equation 45)204... 

Merck has used a diastereoselective double RCM in the synthesis of NK-1 receptor antagonists (Scheme 28.3).33 Previously reported studies by the same group showed that amino acid-derived tetraene 12 smoothly underwent ring closure in a diastereoselective fashion to give the corresponding spirocyclic compounds 13 in excellent diastereoselectivity.34 An extension of this work to the tetraene system derived from phenylglycine gave the desired spirocycle in 86% yield and 70% ds. 

A variety of spirocyclic ethers were prepared by double RCM of the appropriate polyalkene <01SL357> (Scheme 39). The yields of these processes were generally excellent and modest diastereoselection was observed in some cases. 

Procter reported the diastereoselective spirocyclisation of unsaturated ketones 163 using Sml2-43 165 The cyclisation proceeds by conjugate reduction, Sm(III) enolate generation and chelation-controlled aldol cyclisation to give, vyrt-spirocyclic cyclopentanols 164 in good yield (Scheme 5.106). It is important... 

Renaud and coworkers applied a radical addition/translocation/cyclization cascade as a key step in the diastereoselective synthesis of the spirocyclic compound (—)-erythrodiene 168 (Scheme 2.30). Addition of photogenerated PhS to the terminal... 

Finally, the carbometallation reaction of spirocyclic cyclopropenes with a chiral ketal attached to the substrate was described. Thus, carbocupration of the chiral cyclopropene 96 proceeded with 96% diastereoselectivity with a higher-order organocuprate [134] (Scheme 7-114). 

A similar high diastereoselectivity is obtained in the catalytic hydrogenation of spirocyclic ketone 7. Delivery of hydrogen proceeds exclusively from the face of the double bond opposite the isopropyl group19. 

A variety of different tactics have been used to establish all-carbon spirocyclic moieties at oxindole C3. Overman and Watson have conducted an extensive investigation of intramolecular Heck reactions leading to the diastereoselective formation of spirocyclic dioxindoles, e.g., Ill and 114 (Scheme 29) [67-69]. Interestingly, while sequential Heck cyclizations of acetonide protected bis-anilide... 

The Trost group has devised a strategy for stereoselective spirocyclic ring installation across 3-alkylidene oxindoles via palladium-catalyzed [3-1-2] cycloaddition with cyano-substituted trimethylenemethane (Scheme 33) [74, 75]. As illustrated, the opposite sense of diastereoselectivity was observed depending on the choice of chiral ligand 125 or 126. Preferential orientation of the benzenoid portion of the oxindole as dictated by the varied steric environments of the naphthyl ring systems on the catalysts has been put forth as a rationale for the observed difference in stereochemical outcomes. Spirooxindoles 127 and 128 were obtained in 92% ee and 99% ee, respectively. A variation of this methodology has been applied in the racemic synthesis of marcfortine B [75]. 

In an additional variation on the theme of spirocyclization via oxidative rearrangement chemistry, oxidation across the indole 2,3-Jt system has been employed by Martin and coworkers in their approach to the core spirocyclic ring structure of citrinadin A [111]. The key epoxidation/spirocyclization was carried out in diastereoselective fashion using an indole A-chiral auxiliary, (—)-8-phenyl-methol carbamate, to direct the asymmetric event. 

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