Cyclopentene annulation

The first step of the mechanism involves the initial complexation of titanium tetrachloride to the carbonyl group of the electron-deficient alkene (enone) to give an alkoxy-substituted allylic carbocation. The allylic carbocation attacks the (trimethylsilyl)allene regiospecifically at C3 to generate vinyl cation I, which is stabilized by the interaction of the adjacent C-Si bond. The allylic Ji-bond is only coplanar with the C-Si bond in (trimethylsilyl)allenes, so only a C3 substitution can lead to the formation of a stabilized cation. A[1,2]-shift of the silyl group follows to afford an isomeric vinyl cation (II), which is intercepted by the titanium enolate to produce the highly substituted five-membered ring. Side products (III - V) may be formed from vinyl cation I. 

Schafer et al. achieved the formal total synthesis of the trinorguaiane sesquiterpenes ( )-clavukerin and ( )-isoclavukerin by using the Danheiser cyciopentene annulation as the key step. Racemic 4-methylcyclohept-2-en-1-one was reacted with (trimethylsilyl)allene in the presence of 1.7 equivalents of TiCU in dichloromethane at -78 °C to afford a 1 1 mixture of the c/s-fused diastereomers, which were easily separated by HPLC. The diastereomers were then converted to key fragments of earlier total syntheses of the above mentioned natural products. 

Research in the laboratory of R.L. Danheiser has shown that allenylsilanes can be reacted with electrophiles other than enones, such as aldehydes and A/-acyl iminium ions to generate oxygen and nitrogen heterocycles. Aldehydes can function as heteroallenophiles and the reaction of C3 substituted allenylsilane with the achiral cyclohexane carbaldehyde afforded predominantly c/s-substituted dihydrofurans. 

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In a similar manner, terminal alkynes such as 1-14 participate in a Prins/pinacol reaction, resulting in a ring-expanding cyclopentene annulation to give compounds such as 1-15 in high yield (Scheme 1.5) [5]. 

The (trimethylsilyl)cyclopentene annulation proceeds most efficiently with the use of 1-substituted (trimethylsilyl)allenes. Even the fully methyl-substituted (tri-methylsilyl)allene reacted with both cyclic and acyclic enones to provide the corresponding cyclopentenes in good yields. 

Hudlicky, T., Reddy, D.B., Govindan, S.V., Kulp, T., Still, B. and Sheth, J.P., Intramolecular cyclopentene annulation. 3. Synthesis and carhon-13 nuclear magnetic resonance spectroscopy of bicyclic cyclopentene lactones as potential perhydroazulene and/or monoterpene synthons. J. Org. Chem., 1983, 48, 3422. 

In 1986, we found that alkynyl-A3-iodanes serve as good Michael acceptors toward soft nucleophiles, because of the highly electron-deficient nature of the /3-acetylenic carbon atom. This conjugate addition of nucleophiles constitutes a key step of a highly versatile cyclopentene annulation of alkynyl-A3-iodanes via the tandem Michael-carbene insertion (MCI) reaction [Eq. (103)] [185]. 

As shown above, insertion of alkylidene carbenes is highly regioselective. However, when the normal 1,5-C-H insertion pathway is blocked, 1,4- or 1,6-C-H insertion takes place [Eq. (109)]. Thus, the cyclobutene 121 [192] and the six-membered enol ether 123 [193] were obtained in modest yields. Intramolecular insertion into carbon-carbon double bond provides a method for synthesis of cyclopenten-annulated dihydropyrrole 124, which results from homolytic scission of a methylenecyclopropane intermediate [194]. 

Cyclopentenes are commonly formed in the reaction of the appropriate alkynyliodonium salts with enolate anions. Various alkynyliodonium tetrafluo-roborates interact with / -dicarbonyl enolates to give products of cyclopentene annulation in 50-90% yield [121]. Several examples of such annulations are shown in Scheme 59. The carbene cyclization can also occur when the long alkyl... 

The cyclopentene annulations can also occur in the reactions of alkynyliodo-nium salts with nitrogen- and sulfur nucleophiles (Scheme 61). Specifically, azi-docyclopentene 155 is formed upon treatment of octynyliodonium tosylate 154 with sodium azide in dichloromethane [123]. The reaction of alkynyliodonium salt 156 with sodium toluenesulfinate results in the formation of substituted indene 157 via alkylidene carbene aromatic C-H bond insertion [124]. 

Bicyclizations of structurally analogous 5-hydroxy-1-pentynyliodonium tri-flates 34 to cyclopentene-annulated tetrahydrofurans 35 have also been reported (Scheme 56) [157]. Because the strained enol ether moiety in 35 is acid sensitive, these compounds were converted to their monobenzyl ketals. In general, bicyclizations of 34 are less efficient and less versatile than those of the tosylamido analogs. 

Two MCI patterns have been recognized28, one in which the alkyl chain for carbenic insertion is provided by the alkynyliodonium ion (i.e. [5 + 0] cyclopentene annulation ) and another in which the alkyl chain is provided by the enolate ion (i.e. [2 + 3] cyclopentene annulation ). Generic transformations of each type are illustrated in equations 116 and 11728. 

The MCI cyclopentene annulations proceed with moderate efficiency and have been utilized for the construction of polycyclic molecules with fused, spiro and tethered ring systems (e.g. equations 118-120)28. With bis(phenyliodonium) diyne salts, biscyclopentene annulations are observed (e.g. equation 121)86. 

Trost developed a general method of synthesis of vinylcyclqnopanes (and their sulfur and oxygen analogs) through the application of ylide addition to carbmyl compounds. Three major methods involve the cyclopentene annulation, cyclobutanone synthesis, and ring expansion with concomitant alkylation (Scheme 51). °... 

Danheiser cyclopentene annulation Formation of cyclopentenes from enones and allenes. 124... 

Danheiser, R. L., Carini, D. J., Basak, A. (Trimethylsilyl)cyclopentene annulation a regiocontrolled approach to the synthesis of five-membered rings. J. Am. Chem. Soc. 1981, 103, 1604-1606. 

A recent example of a cyclopentene annulation utilizing flash-vacuum pyrolysis led to hydrocarbons of medium molecular weight, e.g. 39 and 40. The practical limit of this particular method is defined by the volatility of the starting vinylcyclopropanes under high vacuum (approximately 400-500 MW at lO Torr). 

The use of (trimethylsilyl)allenes in a (trimethylsilyl)cyclopentene annulation was described in Section 1.6.1.2.3.1 and was shown to occur with a number of electron-deficient olefins6. The following example illustrates the extent to which stereochemistry in the olefinic acceptor can influence the course of the addition. Thus, in the addition to carvone, one diastereomeric product is obtained as a result of attack by the silylallene on the face of the double bond opposite to the isopropenyl unit. 

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