Spirocyclic 3,7 -unsaturated

In a formal synthesis of fasicularin, the critical spirocyclic ketone intermediate 183 was obtained by use of the rearrangement reaction of the silyloxy epoxide 182, derived from the unsaturated alcohol 180. Alkene 180 was epoxidized with DMDO to produce epoxy alcohol 181 as a single diastereoisomer, which was transformed into the trimethyl silyl ether derivative 182. Treatment of 182 with HCU resulted in smooth ring-expansion to produce spiro compound 183, which was subsequently elaborated to the desired natural product (Scheme 8.46) [88]. 

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],... 

Although cyclic azoalkanes are well known as biradical precursors [159] they have been used as 1,2- and 1,3-radical cation precursors only recently [160-164]. Apart from the rearrangement products bicyclopentane 161 and cyclopentene 163, the PET-oxidation of bicyclic azoalkane 158 yields mostly unsaturated spirocyclic products [165]. Common sensitizers are triphenyl-pyrylium tetrafluoroborate and 9,10-dicyanoanthracene with biphenyl as a cosensitizer. The ethers 164 and 165 represent trapping products of the proposed 1,2-radical cation 162. Comparison of the PET chemistry of the azoalkane 158 and the corresponding bicyclopentane 161 additionally supports the notion that the non-rearranged diazenyl radical cation 159 is involved (Scheme 31). 

In continuation to this, they used ot,(3-unsaturated (3-lactams 79 for the construction of spirocyclic compounds 80-82 (Scheme 21) by the addition of a methylene... 

A novel approach to enantiopure spirocyclic (3-lactams has been developed by Alcaide et al. [106] using different intramolecular metal catalyzed cyclization reactions with monocyclic unsaturated alcohols 142 (Scheme 35). Ring-closing metathesis is one of the most powerful and reliable methods to construct a ring system. Transformation of alcohols in diolefin precursors followed by ring-closing... 

The latter example (reaction 36) already indicates that the Yang cydization can also be used to synthesize four-membered heterocycles. After light absorption, the a,(3-unsaturated carbonyl compound 84 undergoes intramolecular hydrogen abstraction at the a-position of the carbonyl moiety (reaction 37), leading to the 1,4-biradical intermediate XXX [87]. A radical combination then efficiently yields the spirocyclic P-lactam derivative 85, and only one stereoisomer is formed in this case. In this transformation, the a,P-unsaturated carbonyl function can be considered as being vinylogous to a simple ketone. 

In all the following examples, the targeted double bonds were activated by suitable substituents to increase the efficacy of the desired cyclization mode. For the total synthesis of acutumine (26), an activated a,p-unsaturated ketone 27 was chosen as precursor (Scheme 10) [74, 75], Aryl radical additions to this type of alkenes are known to proceed about ten times faster than to comparable allylic alcohols. In a radical-polar crossover reaction, the spirocyclic product 28 was obtained in the presence of triethylaluminum as promoter and an oxaziridine as hydroxylating agent. The fact that even the efficient hydrogen donor tetrahydrofuran could be used as solvent nicely demonstrates the high efficacy of the cyclization step. 

Mattay et al. used triethylamine as electron donor in tandem fragmentation/cyclization reactions of a-cyclopropylketones (49) [48]. The initial electron transfer to the ketone moiety is followed by subsequent cyclopropylcarbinyl-homoallyl rearrangement yielding a distonic radical anion (50). With an appropriate unsaturated side chain attached to the molecule both annelated and spirocyclic ring systems are accessible in moderate yields. Scheme 26 shows some representative examples. 

Spiropiperidine Alkaloids.—The spirocyclic keto-base (18), which possesses a histrionicotoxin skeleton, undergoes an acid-catalysed retro-Mannich reaction, followed by re-condensation, to afford the unsaturated imine (19), with a pumiliotoxin skeleton. A mechanism for the transformation has been proposed.29... 

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... 

As with other intramolecular ene reactions, this reaction is best suited to the preparation of cyclopentanes, but can also be used for the preparation of cyclohexanes. The reaction cannot be used for the formation of cyclopropanes or cyclobutanes since the unsaturated carbonyl compound is more stable than the ene adduct. 8,e-Unsaturated ketones (167) do not give cyclobutanes (171) by enolization to give (170) followed by a type I reaction but instead give cyclohexanones (169) by enolization to give (168) followed by a type II reaction. Alkynes can replace alkenes as the enophile. Enols can be prepared from pyrolysis of enol esters, enol ethers and acetals and from -keto esters and 1,3-dicaibonyl compounds. Tlie reaction is well suited to the preparation of fused or bridged bicyclic and spirocyclic compounds. Tandem ene reactions in which two rings are formed in one pot from dienones have also been described. The examples discussed below 2-i63 restricted to those published since Conia and Le Perchec s 1975... 

In a third category of cyclic 3, y-enones of synthetic potential, the chromophore moieties are linked by a spiro carbon typical examples are a 3, y-unsaturated 8-diketone and 3, y 8,e-unsaturated spirocyclic ketones. " A representative of the latter category is (53), which upon triplet sensitization with Mich-ler s ketone affords the isomers (54) and (55) in a ratio of about 2 1 and a total yield of 82% (Scheme... 

Tandem fragmentation-cyclization of bicyclic ketones connected to unsaturated side chains have been used to construct hi-, tri-, and spirocyclic ketones [334], Cossy et al. have shown that depending upon the substitution pattern, ketyl radical anions obtained from photochemically induced electron transfer from amines to cyclopropylketones lead either to the formation of 3-substituted cycloalkanones or to ring expanded products (Scheme 78) [335],... 

Numerous N-alkylnorcodeines have been prepared, and these can be nitrated, acetylated and chlorinated like codeine [361], Other N-substituted norcodeines have also been prepared [362-7], and of these N-aflylnorcodeine and other /3 y-unsaturated derivatives have an action antagonistic to that of morphine [364, 368], A dimolecular derivative results from the interaction of norcodeine and trans A2 3-l 4-dibromo-butene [369]. Spirocyclic quaternary salts such as [li] result from the treatment of norcodeine with pentamethylene iodide, o-xylyldibromide, and /3 /3 di-iododiethyl ether, and these suffer degradation in alkaline solution with fission of the codeine heterocyclic ring [370] (see Chap. VI). 

Additions to a,)S-unsaturated amides are represented by relatively few examples. In the cases shown, the double bond is exocyclic and f urther activated by an ester substituent, but the reactions lead to interesting spirocyclic penicillin 24 and indole 25 derivatives. It should be noted that in both cases, the thermal decomposition proceeds with retention of stereochemistry. 

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