Cyclisations carbonyl-alkene

Sml2-mediated carbonyl- alkene cyclisations are also effective when the alkene contains a (3-substituent. For example, Enholm reported the Sml2-mediated cyclisation of aldehyde 42 in the presence of MeOH to provide the highly functionalised cyclopentanol 43 containing a quaternary stereocentre, in good yield (Scheme 5.32).62... 

Scheme 5.35).65 It is interesting that this is a rare example of a s n-selective carbonyl-alkene cyclisation. 

Finally, Molander has shown that the efficiency of 8-endo carbonyl-alkene cyclisations can be significantly enhanced by the presence of a leaving group in the allylic position of the alkene.57 For example, treatment of allylic acetate 47 with Sml2 provides an excellent yield of the cyclooctenol 48 (Scheme 5.36). After the cyclisation step, the resultant secondary alkyl radical is reduced to an... 

Radical cyclisation-anionic sequences, in which the radical cyclisation involves the addition of a ketyl radical anion to an alkene, are also possible. For example, carbonyl-alkene cyclisation of unsaturated ketone 19 and quenching of the resultant organosamarium with electrophiles allow access to an impressive range of cyclopentanol products (Scheme 6.7).12... 

Pestalotiopsin A and 6-epitaedolidol are structurally related caryophyllene-type sesquiterpenes. In 2003, Procter reported the use of a Sml2-mediated 4-exo-trig carbonyl-alkene cyclisation to construct the core of pestalotiopsin A.57 Treatment of cyclisation substrate 33 with Sml2 in THF, MeOH and 2,2,2-trifluoroethanol gave cyclobutanol products 34 and 35 in good yield and with moderate diastereoselectivity. The major diastereoisomer is believed to arise from a cyclisation in which coordination to the silyl ether group directs addition of the ketyl radical anion to the alkene (Scheme 7.17).57... 

In 2007, Kim reported the first asymmetric synthesis of (+ )-microcladallene B.64 In this approach, the tetrahydropyran ring of the target was prepared by a Sml2-mediated 6-exo-trig carbonyl-alkene cyclisation (Scheme 7.25). The high dia-stereoselectivity of the cyclisation can be rationalised by invoking coordination of... 

In 2003, Molander reported the synthesis of (+ )-isoschizandrin using the Sml2-mediated 8-endo-trig carbonyl-alkene cyclisation of ketone 71 (Scheme 7.30).69 The axial chirality of the biaryl system efficiently controls the central chirality of the product. The (Z)-alkene geometry is also vital to the stereochemical outcome and the presence of HMPA in the reaction mixture helps control the conformation of the transition state by increasing the steric demands of the alkoxysamarium substituent.69... 

Allylic sulfides can also be used as radical acceptors in carbonyl-alkene couplings, as demonstrated by Matsuda in his synthetic approach to graya-notoxin III.23 After cyclisation, the spontaneous expulsion of sulfide installs a new double bond (see Chapter 7, Section 7.4). 

Molander recognised the potential of the Sml2-mediated Barbier addition to esters for the initiation of sequential processes (Chapter 5, Section 5.4). Two types of cascade have been developed that involve nucleophilic acyl substitution the first type involves double intramolecular Barbier addition to an ester group (anionic-anionic sequences),17 and the second type consists of a Barbier addition to an ester followed by a carbonyl-alkene/alkyne cyclisation of the resultant ketone (anionic-radical sequences) (Scheme 6.12).18,19... 

Treatment of the 1,2-oxazines 52 with carbon monoxide at 1000 psi in the presence of cobalt carbonyl brings about insertion of carbon monoxide to form the 1,3-oxazepines S3 <96TL2713>. A convenient route to P-lactams fused to oxepines is made available by alkene metathesis. Thus reaction of 4-acetoxyazetidin-2-one with ally alcohol in the presence of zinc acetate, followed by iV-allylation of the nitrogen affords the derivative 54 which cyclises by RCM to form the oxazepinone 55 <96CC2231>. The same communication describes a similar synthesis of 1,3-dioxepines. 

As is usually the case, intramolecular reactions are easier than intermolecular and often do not obey the usual rules. Some do not need the carbonyl group, some show exo rather than endo selectivity, and the cyclisation of 56 gives the meta product 58. The mechanism 57 makes it clear that the expected para product (cf. 42) cannot be formed. This is a particularly impressive example as the product 58 is a bridgehead alkene with a strained geometry.10 The alkene is cis inside the six-membered ring but trans in the outer 10-membered ring. 

The cyclisation methods we have used so far all depend on the simple disconnection 27a into a carbonyl group and an alkylating agent in the same molecule 28. But the same general class of molecule 27 can be made a very different way that is revealed by disconnection of two C-C bonds 27b to suggest an alkene 29 and a carbene 30. 

The first cyclisations to be put to synthetic use were those of aryl lithiums onto carbonyl compounds, imines and epoxides. These are known as Parham cyclisations , and the method for transforming an aryl bromide to an aryllithium the Parham protocol , after W. E. Parham, who developed the reaction. We will survey the use of Parham cyclisations in synthesis, before assessing intramolecular attack of other electrophiles. The most important of these are the alkenes, and the usefulness of anionic cyclisations onto unactivated double bonds compares very favourably with radical cyclisations, particularly with regard to stereochemical control. 

In 2007, Molander demonstrated that 5-exo-transannular reductive carbonyl addition to an endo- or exocyclic alkene can be highly effective for the formation of bicyclic ring systems. For example, treatment of cyclooctenone 36 with Sml2 and HMPA gave bicyclic alcohol 37 in 70% yield (Scheme 5.28).56 Transannular cyclisations have even been extended to 11-membered carbo-cyclic starting materials and give bicyclic products in good yield. 

Perhaps the most surprising feature of the sequence is that selective reduction of one aldehyde is possible while the other survives to act as an electrophile in the later aldol cyclisation. The necessity for pre-coordination between the aldehyde and the ester carbonyl group of the alkene acceptor prior to electron transfer to the aldehyde could be responsible for this selectivity.16... 

Notice the control inherent in the aldol cyclisation. One from four possible enolates attack one of two carbonyl compounds. This is clearly thermodynamic control under these weakly basic conditions (chapter 5 ). The more highly substituted alkene (here tetra-substituted) and the most stable possible ring (i.e. 5- not 3- or 4-membered) is formed. The geometry of the alkene is of course controlled by the ring.20... 

The imide 189 is easily made from protected tartaric acid 190 and the vinyl silane 188 coupled in a Mitsunobu reaction. Reduction of one of the carbonyl groups of the imide 191 may seem tricky but the molecule is C2 symmetric so the two carbonyl groups are the same and once one is reduced the molecule is a much less reactive amide. The stereochemistry of the acetate in 192 does not matter as it disappears in the cyclisation to 186. Notice that the alkene geometry is retained. 

Previously, tin-ketyl radicals have been added to alkenes only in an intramolecular fashion. [9] In recent publications, however, pinacols and amino alcohols have been prepared by cyclisation of dicarbonyl compounds [10] or keto-oximes [11] with tributyltin hydride. Cyclisation of 1,5-ketoaldehydes 1 and 1,5-dialdehydes with tributyltin hydride yields cw-diols 2 with excellent stereoselectivities, whereas the keto-oxime 4 with four benzyloxy-substituents affords a 58 42 cis trans) mixture. The tran -product was transformed in two more steps to the potent glycosidase inhibitor 1-deoxynojirimycin (6). [lib] The reversibility of both the addition of the tributyltin-radical to the carbonyl group and the intramolecular radical C-C bond formation is believed to be responsible for the high selectivity in the formation of 2. In the cyclisation of 1,5-pentanedial the unhydrolyzed coupling product 3 could be isolated, therefore providing evidence for a new mechanistic variant of the pinacol reaction, in which only 1.2 equivalent of the reducing agent are necessary. 

MPEG with Ru-porphyrin- complexes =0.06-0.14" (via H-NMR) CH2CI2" Alkene epoxidation Alkene cycloprop an ation Cyclisation of a-diazo-carbonyl compounds Alkene aziridination Precipitation (r) Precipitation (diethyl ether) Precipitation (diethyl ether) [141]... 

Propargyl alcohols (17) are efficiently converted to the tranj-3,4-disubstituted chroman (18) via complexation with Co2(CO)8. The key feature of this one-pot procedure is the cyclisation of a cobalt carbonyl stabilised cation by a trisubstituted alkene <97TL685>. 

The reaction was first reported by Khand and Pauson et al. in 1973d It is the dicobalt octacarbonyl [Co2(CO)8l mediated or promoted one-step synthesis of a,p-unsaturated cyclopentenone from the [2+2+1] cycloaddition of alkyne, alkene and carbon monoxide, through an intermediate of alkynedicobalt hexacarbonyl complex. Therefore, this reaction is generally known as the Pauson-Khand reaction, Pauson-Khand cyclization, or Pauson-Khand cycloaddition. Occasionally, this reaction is also referred to as the Pauson-Khand annulation, Pauson-Khand multicomponent cycloaddition, Pauson-Khand carbonylative cocyclization, Pauson-Khand bicyclization, Khand annulation, Khand cycloaddition, Khand cyclization (cyclisation ), or Khand reaction.Among these names, the Pauson-Khand reaction is the one used most often. 

Steroids Carbonyl Compounds Cycloaddition Enone and Dienone Rearrangements Alkenes Isomerisation and Rearrangement Alkenes Cycloaddition Alkenes Photo-oxidation Terpenoids Aromatic Compounds Isomerisation and Cycloaddition Practical Photochemistry Scale-up Aromatic Compounds Substitution and Cyclisation Alkaloids Photoinitiated Free-radical Chain Reactions. 

Ui cyclisation to give 10 and 11 with the stereochemistry as shown in Scheme 3 predominating. Use of either a simple alkene or an enol ether as a radical acceptor proved to be less efficient. 5-Exo cyclisation across a sugar ring has been used to generate cyclopentyl derivatives 12 and 14 (Scheme 4). The nucleophilidty of the C-3 radical derived from 13 corresponds to a reversal of the reactivity normally associated with this electrophilic site (p to a carbonyl moiety). 

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